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ABSTRACT

Glucocorticoids are steroid hormones produced by the adrenal cortex. They have pleiotropic effects and contribute substantially to the maintenance of resting and stress-related homeostasis. Although the molecular mechanisms of their actions are not fully understood, most of glucocorticoid effects are mediated by a ubiquitously expressed transcription factor, the glucocorticoid receptor. The latter influences the transcription rate of several glucocorticoid-target genes or interact physically with other transcription factors regulating their transcriptional activity in a positive or negative fashion. We present the molecular mechanisms of glucocorticoid action, and we discuss glucocorticoid treatment in endocrine and non-endocrine disorders, the side effects of glucocorticoids, their concomitant use and interactions with other drugs, and the risk factors for adrenal suppression. We suggest regimens for weaning patients from long-term glucocorticoid therapy, describe the glucocorticoid withdrawal syndrome, and provide some future perspectives on glucocorticoid treatment. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

INTRODUCTION

Glucocorticoids are steroid hormones produced by the zona fasciculata of the adrenal cortex. These molecules are secreted into the peripheral blood under the control of the hypothalamic-pituitary-adrenal (HPA) axis in an ultradian, circadian and stress-related fashion (1). Glucocorticoids influence a myriad of physiologic functions contributing substantially to the maintenance of resting and stress-related homeostasis. At the cellular level, glucocorticoids regulate proliferation, differentiation and programmed cell death (apoptosis) of various cell types and may change the methylation status of cytosine-guanine dinucleotides (CpG) located in the regulatory regions of many genes, leading to important epigenetic alterations (1, 2).

Although glucocorticoids have been introduced in the treatment of rheumatoid arthritis since 1949, their molecular mechanisms of actions remain an evolving field of molecular and cellular endocrinology. Their anti-inflammatory and immunosuppressive effects are mediated mostly by their cognate receptor, the glucocorticoid receptor (GR), a transcription factor that belongs to the steroid receptor subfamily of the nuclear receptor superfamily (3). The therapeutic applications of synthetic glucocorticoids have been greatly broadened to encompass a large number of non-endocrine and endocrine diseases. Indeed, the prevalence of long-term glucocorticoid use worldwide is estimated at between 1% and 3% of adults (4).

When glucocorticoids are used at supraphysiologic doses, glucocorticoid-induced Hypothalamic-pituitary-adrenal (HPA) axis suppression renders the adrenal glands unable to generate sufficient cortisol if glucocorticoid treatment is abruptly stopped. In addition to adrenal suppression, a growing list of glucocorticoid adverse effects have been documented.

Glucocorticoid resistance has become another limitation in the therapeutic use of glucocorticoids. Our ever-increasing and deeper understanding of the molecular mechanisms of glucocorticoid actions might provide the basis for designing selective GR agonists that will optimize the therapeutic outcome, while minimizing undesired side effects.

MOLECULAR MECHANISMS OF GLUCOCORTICOID ACTION

Within the glucocorticoid target cell, the human (h) GR interacts with heat shock proteins (HSP90, HSP70) and immunophillins (FKBP51 and FKBP52), forming a multiprotein complex. Upon glucocorticoid-binding, the hGR dissociates from its protein partners, translocates into the nucleus, and forms homo- or hetero-dimers that bind to specific DNA sequences, termed “glucocorticoid response elements” (“GREs”), influencing the transcription of several glucocorticoid target genes in a positive or negative fashion (3, 5). For additional information please see the

Endotext chapter on Glucocorticoid receptors (6). Many anti-inflammatory genes are trans-activated by glucocorticoids, while pro-inflammatory genes are trans-repressed by these hormones. Aside from the genomic actions, accumulating evidence suggests that glucocorticoids may exert some effects in a very short time frame, independently of gene transcription and/or translation (7). These nongenomic glucocorticoid effects are believed to be mediated by membrane-bound hGRs that trigger specific kinase signaling pathways (8).

In addition to the above-mentioned actions, glucocorticoids can influence gene expression independently of hGR binding to DNA. These actions are mediated by physical interaction between the monomeric hGR with other transcription factors, such as the nuclear factor κB (NF-κB), the activator protein 1 (AP-1), and the signal transducers and activators of transcription (STATs), influencing the transcription rate of target genes of the latter (3, 5, 6).

SYNTHETIC GLUCOCORTICOIDS

Since the introduction of glucocorticoids (GCs) in the treatment of rheumatoid arthritis in 1949, intense efforts have been made by science and industry to maximize the beneficial effects and minimize the side effects of glucocorticoids. Thus, many synthetic compounds with glucocorticoid activity were manufactured and tested (9). The pharmacologic differences among these chemicals result from structural alterations of their basic steroid nucleus and its side groups. These changes may affect the bioavailability of these compounds - including their gastrointestinal or parenteral absorption, plasma half-life, and metabolism in the liver, fat, or target tissues - and their abilities to interact with the glucocorticoid receptor and to modulate the transcription of glucocorticoid - responsive genes (10, 11). In addition, structural modifications diminish the natural cross-reactivity of glucocorticoids with the mineralocorticoid receptor, eliminating their undesirable salt-retaining activity. Other modifications increase glucocorticoids' water solubility for parenteral administration or decrease their water solubility to enhance topical potency (11).

Synthetic GCs' clinical efficacy depends on their pharmacokinetics and their pharmacodynamics. Pharmacokinetic parameters such as the elimination half-life and pharmacodynamic parameters such as the concentration producing the half-maximal effect determine the duration and intensity of GC effects (12). It is known that the presence of an 11β-hydroxyl group is essential for the anti-inflammatory and immunosuppressive effects of GCs and for the sodium retaining effects of the mineralocorticoids (MCs). The most important pharmacokinetic systems for GCs and MCs are the 11β- hydroxysteroid dehydrogenases (11β-HSDs) because they regulate the target cell adjustment between the active hydroxy- and the inactive oxo- form of a steroid (13, 14). 11β- hydroxysteroid dehydrogenase type 2 (11β-HSD2, oxidizing enzyme) catalyzes the conversion of cortisol to cortisone, the inactive metabolite, whereas 11β- hydroxysteroid dehydrogenase type 1 (11β-HSD1, reductase) converts cortisone to cortisol. Thus, 11β-HSD1, which is expressed in a wide range of tissues, mainly in the liver, facilitates GC hormone action whereas the major role of 11β-HSD2 is to prevent cortisol from gaining access to high-affinity MC receptors and, therefore, the enzyme is predominantly expressed in the MC responsive cells of the kidney and other MC target tissues (colon, salivary glands) and the placenta (13).

The main structural features determining GC potency are the size and the polarity of the substituent in position 6 or 16. A hydrophobic residue increases GC activity (statistically significant enhancement with 6-α methyl and 16-methylene substitution). The more polar 16-hydroxy substitution decreases GC potency. The 6α and 9α-fluorination (such as in 6α and 9α fluorocortisol respectively) leads to increased GC and MC activity and double fluorination in the same positions augments this shift. Moreover, the Δ1-dehydro-configuration (in prednisolone) enhances GC activity but opposite to that effect it attenuates MC potency. The same effect is observed with the 16-methylene, 16α-methyl (dexamethasone) and 16β-methyl (betamethasone) groups. Thus, the more selective GC transactivation activity of GCs with a 16α-methyl or 16β-methyl group and a Δ1-dehydro-configuration, results from a significantly decreased activity via the mineralocorticoid receptor (MR) and an enhanced activity via the glucocorticoid receptor (GR) (15). Moreover, whereas GC selectivity can be improved by hydrophobic substituents in position 16 and the Δ1-dehydro-configuration, maximal GC activity needs additional fluorination in position 9α (such as in dexamethasone) (16). Figure 1 presents the chemical structures of cortisol and the most commonly used synthetic GCs.

Figure 1: Chemical Structures of the Most Commonly Used Synthetic GCs.

Protein binding is another pharmacokinetic property that influences GCs biological activity because only the unbound GC fraction is biologically active (14). In humans, endogenous cortisol binding to cortisol binding globulin (CBG) ranges between 67% and 87%, whereas a further 7-19% of total cortisol is bound to albumin, leading to about 95% of cortisol being protein-bound in the plasma. Except for prednisolone, synthetic GCs bind predominantly to albumin and only marginally to CBG. Plasma binding e.g. of dexamethasone and betamethasone is 75% and 60% respectively, and this is quite constant across a wide concentration rate (17). Thus, CBG binding is not a major determinant of plasma and biological half-lives of synthetic GCs.

However, especially for hydrocortisone and prednisone, pharmacokinetics are non-linear due to protein binding. As a result, higher doses result in more rapid clearance rates. It has to be mentioned that prednisone itself is biologically inactive and its 11-keto group must be reduced by hepatic 11βHSD1 to form the active drug, prednisolone. Moreover, clearance rate depends on age and is more rapid in children than adults (18) and also depends upon individual variability. Finally, certain diseases may influence synthetic GCs' pharmacokinetics. Thus, clearance is reduced particularly in renal and hepatic diseases and hypothyroidism and increased in hyperthyroidism. The concomitant use of other drugs influences synthetic GCs' half-lives and, thus, their final effect in target tissues (18, 19). Classic bioassays measure synthetic GC potency by testing the ability to suppress eosinophils and inhibit inflammation and the ability to stimulate hepatic glycogen deposition. The biologic effective half-life of glucocorticoids divides them into short-, intermediate-, or long-acting, based on the duration of corticotropin suppression after a single dose of the compound. The main corticosteroids used in clinical practice together with their relative biologic potencies and their plasma and biological half-lives are listed in Table 1.

Table 1: Glucocorticoid Equivalencies (11, 20, 21)

Glucocorticoids

Equivalent dose (mg)

Gluco-corticoid potency

HPA Suppression

Mineralo-corticoid potency

Plasma

half-life

(min)

Biologic half-life (h)

Short-acting

Cortisol

20.0

1.0

1.0

1.0

90

8-12

Cortisone

25.0

0.8

0.8

80-118

8-12

Intermediate-acting

Prednisone

5.0

4.0

4.0

0.3

60

18-36

Prednisolone

5.0

5.0

0.3

115-200

18-36

Triamcinolone

4.0

5.0

4.0

0

30

18-36

Methylprednisolone

4.0

5.0

4.0

0

180

18-36

Long-acting

Dexamethasone

0.75

30

17

0

200

36-54

Betamethasone

0.6

25-40

0

300

36-54

Mineralocorticoids

Fludrocortisone

2.0

10

12.0

250

200

18-36

Desoxycorticosterone acetate

0

20

70

SYSTEMIC GLUCOCORTICOID ADMINISTRATION

Therapeutic Indications

GCs are used in both endocrine and non-endocrine disorders (11, 22). First of all, they are administered as replacement therapy in patients with primary or secondary adrenal insufficiency, and as adrenal suppression therapy in congenital adrenal hyperplasia and glucocorticoid resistance (11). They are also used in patients with Grave's opthalmopathy and for some diagnostic purposes such as in establishing Cushing's syndrome (11). Moreover, due to their immunosuppressive and anti-inflammatory properties they are used in a broad range of non-endocrine disorders affecting many different systems (22, 23). Thus, they are given to treat skin disorders such as dermatitis and pemphigus, rheumatologic diseases such as systemic lupus erythematosus, polyarteritis and rheumatoid arthritis, and also polymyalgia rheumatica and myasthenia gravis. In hematology, they are used, along with chemotherapy, for the treatment of lymphomas and leukemias (24) and in hemolytic anemias and idiopathic thrombocytopenic purpura. In addition, they are administered in gastrointestinal diseases such as inflammatory bowel disease, in liver diseases (chronic active hepatitis) and in respiratory diseases (angioedema, anaphylaxis, asthma, sarcoidosis, tuberculosis, obstructive airway disease). Moreover, GCs are used in nephrotic syndrome and vasculitis and also in the suppression of the host-versus-graft and graft-versus-host reaction in cases of organ transplantation. In nervous disorders such as cerebral edema and raised intracranial pressure the use of GCs is also beneficial (25, 26).

Acute administration of pharmacologic doses of glucocorticoids is advocated in a small number of nonendocrine diseases, such as for patients suffering from acute traumatic spinal cord injury, although two recent meta-analyses support that the use of methylprednisolone should be limited (27, 28). Moreover, steroid administration should be considered as a post-operative additional therapy for cases with severe neurological deficits even after surgery (29). Glucocorticoids are also used for postoperative pain relief after severe bone operations (30). In addition, as it is known that premature birth is associated with an increased risk of neonatal mortality and morbidity, including respiratory distress syndrome (RDS), and because 7-10% of all pregnancies in North America are under such risk, in 1994 the National Institutes of Health (NIH) Consensus Developmental Conference on the Effects of Corticosteroids for Fetal Maturation on Perinatal Outcomes concluded that all fetuses between 24 and 34 week gestation at risk of preterm delivery should be considered as candidates for antenatal treatment with GCs. Recommended treatment consisted of 2 doses of 12mg betamethasone given IM 24 hours apart or 4 doses of 6mg dexamethasone given 12 hours apart. In 2001 the NIH Consensus Developmental Panel recommended that repeat courses should not be used routinely until insightful findings are available. However, the Australian Collaborative Trial (ACTORDS), that has been completed, reported that repeat course synthetic GCs improved short-term neonatal outcome compared to single course therapy (31).

Acute administration of pharmacologic doses of glucocorticoids is also necessary in some types of acute illness. For years it is known that any type of acute illness or trauma results in loss of the diurnal variation in cortisol secretion. In the early phase of critical illness cortisol levels frequently rise and levels of CBG and albumin are substantially depleted. In the chronic phase of critical illness, however, high ACTH and cortisol levels are generally sustained and CBG levels gradually increase. Both very high and very low cortisol levels have been associated with increased mortality from critical illness. High cortisol levels reflect severe stress, whereas low levels reflect an inability to sufficiently respond to stress (32). The term "critical illness-related cortisol insufficiency" (CIRCI) defines a state of both the inadequate production of GCs as well as a corticosteroid tissue resistance. It has been estimated that the overall incidence of adrenal insufficiency in critically ill patients is approximately 20%, with an incidence as high as 60% in patients with severe sepsis and septic shock. It is possible that CIRCI is an epiphenomenon and a marker of illness severity (33).

According to the current recommendations, CIRCI should be suspected in hypotensive patients who respond poorly to fluids and vasopressor agents, particularly in the setting of sepsis. To diagnose CIRCI, the clinician may use a delta serum cortisol <9 μg/dl after cosyntropin (250μg) administration or a random plasma cortisol <10μg/dl. The authors suggest that clinicians should not use plasma-free cortisol or salivary cortisol level over plasma total cortisol. For patients with septic shock that is not responsive to fluid and moderate- to high-dose vasopressor therapy, the authors suggest IV hydrocortisone < 400 mg/day for ≥ 3 days at full dose. They, however, do not suggest using corticosteroids in adult patients with sepsis without any evidence of shock. The dose regimen in patients with early moderate to severe ARDS is methylprednisolone 1mg/kg/day for at least 14 days. Finally, glucocorticoids are not suggested for cases of major trauma (34). In a second part of the guidelines, the authors formulated statements for or against the use of synthetic corticosteroids for other common pathologic conditions, including community-acquired pneumonia, influenza, meningitis, and non-septic systemic inflammatory response syndrome (SIRS) that may be associated with shock, namely burns, cardiac arrest and cardiopulmonary bypass surgery (35).

Benefits of GCs replacement has been demonstrated in a number of other patient populations including low cardiac output syndrome after cardiac surgery (36), acute exacerbation of chronic obstructive pulmonary disease (37), and cirrhosis (38).

Adverse Effects (AEs)

Although synthetic GCs remain an important component of therapy for many conditions, in recent years there are arguments against their use based mainly on the concern of toxicity. Nowadays, GCs toxicity is one of the commonest causes of iatrogenic illness associated with chronic inflammatory disorders. Despite the fact that the adverse effects of GCs have been known for decades, the actual risk-benefit ratio is incomplete and/or inconsistent. This happens because it is in general difficult to separate the effects of GCs from the outcome of the underlying disease, other comorbidities, or the use of other medications. Moreover, toxicity reports usually concern patients using high doses of GCs, different types of GCs with different relative drug potencies, for a heterogeneous group of related diseases, and for different periods of time (39, 40).

Only recently there has been intense effort by scientists and clinicians to explore and quantify the incidence and severity of the AEs of GC therapy. Generally, it is known that GCs' toxicity is related to both the average and cumulative dose during their use (41). The question that arises is whether or not patterns relating the frequency of AEs to GC dosage and/or length of GC treatment exist (39).

Historically, GCs at a prednisone equivalent of 5-10mg/day are considered low dose. However, a review of "the 4 extensively reviewed trials on low dose GCs in rheumatoid arthritis" led to the conclusion that definitive association of low dose GCs with many AEs such as osteoporosis, myopathy, cardiovascular disease, glaucoma, increased incidence of any kind of infection, and behavior disturbances remains elusive, and that the fear of GCs toxicity is probably overestimated based on extrapolation from observations with higher dose treatment. However, according to the same analysis, the use of 5-10mg/day of prednisolone (or equivalent) for over 2 years is associated with an increase of mean body weight in the range of 4-8% (40).

The prevalence of GC associated AEs was identified in a large survey of 2167 long term (≥60 days) users of GCs with mean prednisone equivalent dose of 16±14mg/day. The AE with the greatest prevalence was weight gain, experienced by 70% of the individuals, followed by skin bruising/thinning, and sleep disturbances. Cataracts (15%) and fractures (12%) were among the most serious AEs. All AEs demonstrated a strong dose-dependent association with cumulative GC use. Acne, skin bruising, weight gain and cataracts were significantly associated with longer duration (>90 days) of low-dose GCs (≤7.5mg/day of prednisolone), while fractures and sleep disturbances were more strongly associated with small increments in daily dosage (within the 0-7.5mg/d range). In conclusion, this survey adds further evidence that more GC associated AEs are dependent on both the average dose and the duration of therapy and that even low dose GC therapy could lead to serious AEs (42).

As in more severe cases of chronic inflammatory diseases long-term (≥ 1month) dosage of GCs is medium to low (≤30mg/d prednisolone or equivalent), a systematic review of 28 studies (2382 patients) concerning patients with rheumatoid arthritis (RA), polymyalgia rheumatica, and inflammatory bowel disease was the first to present a pooled analysis of the commonest reported AEs associated with this pattern of administration. The AE rate depends both on the quality of the study and primarily- on the disease in the study population. The overall mean rate of AEs was 150 per 100 patient-years, varying from 43/100patient years in rheumatoid arthritis and 80/100patient years in polymyalgia rheumatica to 555/100 patient years in inflammatory bowel disease. Psychological and behavioral disturbances (e.g. minor mood disturbances) were most frequently reported, followed by gastrointestinal events (e.g. dyspepsia, dysphagia) (43).

A recent retrospective population-based cohort study and self-controlled case series aimed to assess the risk of sepsis, venous thromboembolism, and fracture in 327,452 adults aged 18 to 64 years who received at least one prescription for less than 30 days over a three-year period (44). The authors found increased rates of sepsis (incidence rate ratio 5.30, 95% confidence interval 3.80 to 7.41), venous thromboembolism (3.33, 2.78 to 3.99), and fracture (1.87, 1.69 to 2.07), which decreased within the next 90 days. The increased risk for these adverse effects was observed at prednisolone doses lower than 20mg per day (44).

An important observational study aimed to identify patterns of self-reported health problems relating to dose and duration of GCs in 1066 unselected patients with RA (39). The study identified 2 distinct dose-related patterns of AEs. A continuous, approximately linear rising with increasing dose was found for cushingoid phenotype, ecchymosis, leg edema, mycosis, parchment-like skin, shortness of breath, and sleep disturbance. The most clearly attributable adverse drug reaction to GCs, Cushing syndrome, becomes evident after at least one month of treatment and was observed in 2.7, 4.3, 15.8, 24.6% of patients with no GCs in the past 12 months, and <5, 5-7,5 and >7,5mg/d of prednisolone or equivalent for >6 months, respectively. The second pattern identified describes an elevation in the frequency of health problems beyond a certain threshold value and is defined as a "threshold pattern". The threshold for the increase in glaucoma, depression, and an increase in blood pressure was observed at dosages of greater than 7.5mg/d. Dosages of 5mg/d or more were associated with epistaxis and weight gain. A very low threshold was observed for eye cataract (<5mg/d). All the associations found are in agreement with biological mechanisms and clinical observations (39). However, more extensive research on the risk-benefit ratio of long-term GCs is needed and could help to create new targets for drug development.

An overview of the most common and most serious AEs associated with GC therapy is discussed below.

ADRENAL INSUFFICIENCY (AI)

Iatrogenic, tertiary adrenal insufficiency induced by chronic administration of high doses of GCs is the most common cause of adrenal insufficiency (45). Physiologically, the hypothalamus secretes CRH which stimulates the release of ACTH from the anterior pituitary. ACTH leads to the release of cortisol from the zona fasciculata of the adrenal gland, which in turn exerts negative feedback on CRH and ACTH release. Administration of exogenous GCs even in small doses for only few days leads to a measurable suppression of the HPA axis by decreasing CRH synthesis and secretion and by blocking the trophic and ACTH-releasing actions of CRH on the anterior pituitary. This leads to suppressed synthesis of POMC, ACTH and other POMC derived peptides and later, to the atrophy of the corticotrophin cells of the anterior pituitary. As a result, in the absence of ACTH, the adrenal cortex loses the ability to produce cortisol. Nevertheless, the adrenal cortex retains the ability to secrete enough cortisol for some period of time and also mineralocorticoids, as this latter function depends mainly on the renin-angiotensin system rather than on ACTH.

The association between AI and treatment with oral GCs has been recognized for decades, although the magnitude of the risk has not been determined until recently. It has also been reported that the inhibition of the HPA axis function induced by exogenous GCs may persist for 6 to 12 months after treatment is withdrawn (46). Based on the literature the absolute risk of adrenal crisis after cessation of oral and inhaled GCs might be considered rare, but it is likely to be substantially underreported in clinical practice (10, 47).

The first study that quantified the increased risk of AI in people prescribed oral and inhaled GCs in the general population was published in 2006 (48). This case-control study, that used data from a cohort of 2.4 million people, found a strong dose-response relationship between oral GCs exposure and the risk of AI with an OR of 3.4 (95% CI, 1.6-2.5) per course of treatment per year. Furthermore, the study indicated, that administration of inhaled GCs within 90 days of diagnosis is associated with an increased risk of AI (OR 3.4, 95% CI 1.9-5.9) and this effect was dose related. However, after adjustment for oral GCs exposure, this association was reduced (OR 1.6, 95% CI 0.8-3.2) although the dose relation remains. The largest increase in risk occurred in association with a recent prescription for fluticasone proprionate (48). These findings were confirmed by more recent studies that aimed to investigate the prevalence of AI in patients treated either with inhaled (49) or with oral GCs (47, 50). Interestingly, in a recently published systematic review the authors found that the percentage of patients with glucocorticoid-induced AI had a median (IQR) of 37.4%, ranging from 13%-63% (51). Three years after glucocorticoid withdrawal, AI persisted in 15% of retested patients. AI occurred in patients receiving <5mg prednisolone equivalent dose/day, for less than 4 weeks, and with a cumulative dose <0.5g (51).

CARDIOVASCULAR DISEASE

A population-based study that compared the risk for CVD in 68,781 patients using GCs versus 82,202 nonusers identified that the relative risk for a cardiovascular event in patients receiving high-dose GCs (≥7,5mg/d prednisolone) was 2.56 (CI 2.18-2.99) after adjustment for known covariates (52). Similar associations were noted in another observational study that included 50,656 patients and an equal number of matched controls. According to this study, current use of GCs was associated with an increased risk of heart failure (OR 2.66, 95% CI 2.46-287) and a smaller risk of ischemic heart disease (OR 1.20, 95% CI 1.11-1.29) (53). However, the previous results are not confirmed by other studies (54, 55). Additionally, an association of GCs use and the risk for atrial fibrillation and flutter has been established by several studies (56-58).

GLUCOSE HOMEOSTASIS

The alterations in glucose homeostasis induced by GCs are multifactorial and could be explained by several potential mechanisms including the induction of enzymes involved in hepatic gluconeogenesis, the decrease in glucose uptake in peripheral tissues, the stimulation of lipolysis, the prevention of insulin production, and the induction of ceramide biosynthesis leading to insulin resistance (59). An interesting review of the existing literature published between 1950-2009 shows that GC-induced hyperglycemia is common among patients with and without diabetes mellitus. The OR for new onset diabetes mellitus ranges from 1.5 to 2.5 and the induction of the disease is strongly predicted by GC accumulative dose and duration of therapy (60).

INFECTIOUS EVENTS

GC therapy is associated with an increased risk of infectious complications, as GCs are known to have suppressive effects upon both innate and acquired immunity. This is confirmed by several studies. According to a large observational study of 16,788 patients with RA, prednisone use, even at doses of 5mg/kg, increased the risk of hospitalization for pneumonia. Furthermore, there was a dose related relationship between prednisone use and pneumonia risk in RA (61). Another study of 15,597 patients with RA found that GC use doubled the rate of serious bacterial infections compared with methotrexate with a dose response relationship for doses greater than 5mg/d (62). The latter results were confirmed by additional studies that have identified GCs as an independent risk factor for infections (63, 64). Moreover, a more recent study demonstrated that patients receiving 5mg prednisolone continuously for the last 3 months, 6 months or 3 years, had a 30%, 46% or 100% increased risk of serious infection, respectively (65). Also, caution about GC use in patients with active or dormant TB is well accepted as these individuals are susceptible to contract or to sustain activation of the disease (66). An epidemiological study of patients with TB showed that they were nearly 5 times more likely to have been using GCs at the time of their diagnosis (67).

OSTEOPOROSIS

The effects of GCs on bone homeostasis are both systemic and local. Systemic effects include a reduction in calcium absorption from the intestine and a reduction in calcium reabsorption in the kidney, both enhancing PTH secretion and thus bone loss. Furthermore, the attenuation of sex steroids and growth hormone by GCs enhances bone loss. The direct effects of GCs on bone cells include induction of osteoblast and osteocyte apoptosis through activation of pro-apoptotic molecules, impairment of Wnt signaling, and induction of RANKL, a potent stimulator of osteoclastogenesis produced by osteoblasts (68). As a result, GCs induced osteoporosis is the most common type of iatrogenic osteoporosis. This has been confirmed by several studies. One of them showed that therapy with high-dose oral GCs caused significant decrease in BMD even in the first 2 months of therapy (69). As a result, there is an increased risk of osteoporotic fractures (70) and it has been estimated that fractures may occur in up to 30-50% of patients on GC therapy (71) but fortunately there is a rapid decrease of the risk on cessation of therapy (70, 72). Similar findings were observed by a more recent study showing that low daily dose prednisone (≤7,5mg/d) with high cumulative doses increases the risk for fractures. Intermittent high-dose regimens with cumulative doses less than 1gr, however, did not show an increased risk. Risk declines rapidly, the decrease beginning 3 months after cessation of therapy (73). For additional details please see the Endotext chapter on Glucocorticoid-induced osteoporosis (74).

NEUROPSYCHIATRIC EVENTS

Despite a slight increase in their overall sense of well-being independent of improvement in disease activity, it has been established that synthetic GC treatment may induce behavioral, psychic, and cognitive disturbances (75). These disturbances can be detected by structural, functional, and spectroscopic imaging. Behavioral changes in feeding and sleeping are commonly observed. Among psychic AEs, hypomania and mania are the most common during acute GC therapy and depression during long-term treatment. Suicides have also been reported (76). These AEs are usually mild/moderate but are severe in 5-10% of cases. Cognitive changes affect mostly declarative and working memory. All these AEs are generally dose and time dependent (infrequent at prednisone equivalent doses <20mg/d) and usually reversible. There has to be greater concern for pediatric patients. Several medications such as lithium, phenytoin, lamotrigine, memantine and other anti-seizure, anti-psychotics, and anti-depressants could be useful for treating such disorders (77, 78).

PEDIATRIC EVENTS

Prolonged GC treatment of children with chronic illnesses impairs their longitudinal growth (79). GCs exert multiple growth suppressing effects, such as inhibition of GH secretion and IGF-1 expression, reduction of bone and collagen formation, bone mineralization, and vascularization. These effects are more pronounced with daily oral GCs than alternate day oral GC therapy (80). According to a study of 224 children with cystic fibrosis who have received alternate day treatment with prednisone, boys but not girls, had persistent growth impairment (mean final height 4cm less than children who were treated with placebo) after discontinuation of treatment (81).

Apart from growth retardation, children may also be more susceptible to other AEs associated with GCs such as osteoporosis, glaucoma and cataracts. Moreover, fracture risk seems to be higher in GC-treated children (82).

Intrauterine exposure to GCs is able to affect fetal HPA axis development causing reduction in fetal and, in some cases newborn and infant HPA axis activity under basal conditions and more consistently after pain-related stress. Although baseline HPA axis function seems to recover within the first 2 weeks postpartum, there is initial evidence that blunted HPA axis reactivity to pain-related stress persists throughout the first 4 months of life. These effects are dose dependent and vary with the time between GC exposure and HPA assessment. It seems that programming of the HPA axis involves interaction with other endocrine systems such as the Hypothalamus-Pituitary-Gonadal axis (HPG). Moreover, exposure to GCs during pregnancy has been linked to impaired fetal growth and modulated fetal immune functions, indicators of compromised cognitive, neurological and psychological functions, and increased blood pressure into adolescence. Furthermore, there is some evidence that reduced HPA axis activity early in life will switch to a hyperactive state later in life due to over-adjustment and because of that, affected infants may be vulnerable to stress related disorders associated with hypercortisolemia such as depression and cardiovascular disease. Finally, it seems that changes in HPA axis function following antenatal exposure to GCs are trans-generational and likely involve epigenetic mechanisms (17).

In addition, according to a recent meta-analysis, early postnatal GC treatment (≤7 days), particularly with dexamethasone, causes short term AEs including gastrointestinal bleeding, intestinal perforation, hyperglycemia, hypertension, hypertrophic cardiomyopathy and growth failure (83, 84). Long term follow-up studies report an increased risk of abnormal neurological examination and cerebral palsy (85).

PHEOCHROMOCYTOMA CRISIS

Severe isolated cases of pheochromocytoma crisis have been reported after administration of exogenous GCs (86, 87). Thus, GCs should be avoided or administered only if absolutely necessary in patients with known or suspected pheochromocytomas.

The most common AEs of GC therapy are summarized in Table 2.

Table 2: Common AEs of Glucocorticoid Therapy (88)

Onset early in therapy, essentially unavoidable

Emotional lability

Enhanced appetite, weight gain, or both

Insomnia

Enhanced in patients with underlying risk factors or concomitant use of other drugs

Glucocorticoid-related acne

Diabetes mellitus

Hypertension

Peptic ulcer disease

When supraphysiologic treatment is sustained

Cushingoid appearance

Hypothalamic-pituitary-adrenal suppression

Impaired wound healing

Myopathy

Osteonecrosis

Increased susceptibility to infections

Delayed and insidious, probably dependent on cumulative dose

Atherosclerosis

Cataracts

Fatty liver

Growth retardation

Osteoporosis

Skin atrophy

Rare and unpredictable

Glaucoma

Pancreatitis

Pseudotumor cerebri

Psychosis

COMPARTMENTAL GLUCOCORTICOID ADMINISTRATION

Topical Glucocorticoids

Glucocorticoids are the first line of treatment for various skin disorders such as atopic dermatitis, vitiligo, psoriasis, etc. (10, 89-94). They are quite effective when applied topically and nontoxic to the skin in the short term. The factors that determine local penetration are the structure of the compound employed, the vehicle, the basic additives, occlusion versus open use, normal skin versus diseased skin, and small areas versus large areas of application. Fluorinated steroids (e.g. dexamethasone, triamcinolone acetonide, betamethasone, and beclomethasone) penetrate the skin better than nonfluorinated steroids, such as hydrocortisone. However, fluorinated steroids also produce more local complications and may be associated with systemic absorption and side effects.

The most frequent AEs are local and include atrophy, striae, rosacea, perioral dermatitis, acne, and purpura. Less frequently, hypertrichosis, pigmentation alterations, delayed wound healing, and exacerbation of skin infections occur. Furthermore, the rate of contact sensitization against GCs is greater than previously believed. Systemic reactions such as hyperglycemia, glaucoma and adrenal insufficiency are less frequent (95). Some cases of Cushing's syndrome following overuse of topical GCs have also been described (96). The frequency of systemic effects by topical corticosteroids is increased in newborns and small children compared to adolescents and adults, because GCs penetrate the skin of newborns and small children more easily and in larger proportional amounts. Infants, especially, have a greater risk for Cushing's syndrome or adrenal insufficiency and also hepatosteatosis. An infant's death due to generalized CMV infection following administration of topical GCs has been reported (97). Based on the Body Surface Area, a simple guideline for how much topical GC to prescribe for a child has been proposed. Roughly, infants require one fifth of adults' doses, children two fifths and adolescents two thirds of adults' doses (98). Finally, the use of skin lightning cosmetics used in most African countries includes corticosteroids and may have many serious and sometimes fatal complications, including adrenal insufficiency (99).

Opthalmic Glucocorticoids

In the past 10 years intravitreal GCs injections have been increasingly used for patients with a variety of posterior segment diseases, including diabetic macular edema, branch and central retinal vein occlusion, pseudophakic cystoid macular edema, and uveitic macular edema (100). Currently, novel agents including preservative-free and sustained-release intravitreal implants are being studied in clinical trials. Potential complications of intravitreal steroid treatment are divided into steroid-related and injection-related side effects. Steroid-related side effects include cataract formation and glaucoma (101). Injection related side effects include retinal detachment, vitreous hemorrhage, and bacterial and sterile endopthalmitis.

Inhaled Glucocorticoids

GC inhalation therapy is widely used in patients with asthma and chronic obstructive pulmonary disease. Their relative topical to systemic effect ratio or therapeutic index depends upon the pharmacokinetic differences for inhaled GCs. Factors that enhance the therapeutic index are: decreased oral absorption retention in the lung and rapid systemic clearance once the drug is absorbed into the systemic circulation. More recently, it has been posited that the therapeutic index is also enhanced by high plasma protein binding. Inhaled GCs have important pharmacokinetic differences (102).

In general, inhaled GCs have fewer and less severe AEs than oral and systemic GCs. However, systemic AEs may be observed and this risk is influenced by the dose, the period of treatment, the delivery system used, the site of delivery (i.e. gastrointestinal tract, lung), the concomitant use of other medications, and the altered steroid metabolism due to individual's differences in the patient's response to GCs.

As far as growth deceleration in children is concerned, the results are somewhat contradictory. Although inhaled GCs seem to cause a dose-dependent reduction in height velocity (103), these changes are not significantly associated with final adult height (104). However, a study of 1041 asthmatic children treated with budesonide, nedocromil, and placebo for 4.3 years, a decrease in growth velocity was observed in the budesonide group which was most evident in the first year of treatment (105). When 90% of these children were followed-up for an additional 4.8 years, a lower mean height was found in the budesonide group and this was more pronounced in girls than in boys (106).

Moreover, as GCs effect on bone metabolism is of great concern, some studies have shown that inhaled GC therapy is associated with increased fracture risk (107, 108) but this has not been confirmed by a meta-analysis (109). Nevertheless, several studies confirm a negative relation between total accumulative dose of inhaled GCs and bone mineral density (110). The loss in BMD is of concern, especially in early postmenopausal women and boys during puberty (111, 112). Again, these results have been argued (113).

It has been shown that adrenal insufficiency is also associated with inhaled GCs, although with lower prevalence (114). The newest inhaled GC, Ciclesonide, appears to have different pharmacokinetics enhancing its therapeutic index. It is administered as a pro-drug converted to the active metabolite des-Ciclesonide in the lung. Thus, it has low oral bioavailability and also rapid clearance and high protein binding, factors that reduce pharmacologically relevant systemic exposure (115). Furthermore, Ciclesonide appears to have less suppressive effects on HPA axis function (116, 117).

Nasal Glucocorticoids

Intranasal GCs are effectively used for the treatment of allergic rhinitis, rhinosinusitis, rhinoconjunctivitis, and nasal polyposis (118, 119). Topical steroid drops are used for the treatment of sinus ostia stenosis in the postoperative period (120). Interestingly, molecules designed specifically to achieve potent localized activity with minimum risk of systemic exposure such as mometasone furoate, fluticasone proprionate, and fluticasone furoate may be preferable. Studies in children have not found any adverse effects including HPA axis suppression or growth retardation (118). Yet, some studies suggest a relationship between intranasal steroids and increased intraocular pressure (119). Generally, frequent and chronic use should be avoided to prevent local and systemic complications (121).

Intraarticular Glucocorticoids

The main beneficial effect of intraarticular GC injection is pain relief. Most favorable results are seen in juvenile idiopathic arthritis patients. Local AEs are either rare or insignificant and include joint infection, intraarticular and periarticular calcifications, cutaneous atrophy, cutaneous depigmentation, avascular necrosis, rapid destruction of the femoral head, acute synovitis, Charcot's arthropathy, tendinopathy, Nicolau's syndrome, and joint dislocation (122). Moreover, some systemic AEs have also been reported. These include a transient HPA axis suppression, a transient increase in blood glucose in diabetic patients, and other metabolic, hematologic, vascular, allergic, visual and psychological AEs (123). The most used intraarticular glucocorticoids are triamcinolone hexacetonide, triamcinolone acetonide, and methylprednisolone acetate (124).

MONITORING OF PATIENTS ON GLUCOCORTICOID TREATMENT

As osteoporosis, with resultant fractures, constitutes one of the most serious morbid complications of GC use, worsening patients quality of life, recently, the American College of Rheumatology (ACR) updated the 2010 recommendations for patients receiving oral GC therapy (125). In this systematic review, the authors addressed the initial assessment in patients that began or continue glucocorticoid treatment for longer than 3 months, and discussed the advantages and disadvantages of lifestyle modification, as well as for calcium, vitamin D and pharmaceutical treatment, including bisphosphonates, raloxifene, teriparatide, and denosumab. According to the ACR guidelines, there are three categories of fracture risk. High risk criteria include patients aged over 40 years, previous osteoporotic fracture, hip or spine BMD T-score ≤ −2.5, or 10-year fracture probability of ≥20% (major osteoporotic fracture) or ≥3% (hip fracture) (125, 126). Moderate and low risk criteria are based only on FRAX-derived fracture probability (10–19% and >1 to ≤3% respectively for moderate

risk, and <10% and ≤1% respectively for low risk) (125, 126). In patients aged less than 40 years, a previous osteoporotic fracture is considered as a high-risk criterion, whereas the criteria of moderate and low risk are based on the BMD. Patients at low fracture risk are recommended to receive only calcium and vitamin D, whereas adults at moderate-to-high fracture risk should be treated with calcium and vitamin D plus an oral bisphosphonate. However, adults in whom oral bisphosphonates are not appropriate, are recommended to continue calcium plus vitamin D but switch from an oral bisphosphonate to another anti-fracture medication (125). Finally, adults who complete a planned regimen with oral bisphosphonates and continue glucocorticoid treatment, are recommended to continue oral bisphosphonate treatment or switch to another anti-fracture medication (125). Recommendations were also suggested for children, women of childbearing potential, and people with organ transplants, as well as patients receiving very high doses of glucocorticoids (125). For additional details please see the Endotext chapter on Glucocorticoid-induced osteoporosis (74).

CONCOMITANT USE OF GLUCOCORTICOIDS WITH OTHER DRUGS

Special attention is required in the concomitant use of glucocorticoids with other drugs because of potential interactions, and because some drugs may affect the metabolism of the steroids, which may lead to a decreased or increased glucocorticoid effect on their target tissues (20). Such interactions and effects are shown in Tables 3, 4 and 5.

Table 3: Interactions of Glucocorticoids with Other Drugs (20)

Drug

Side effect

Comments

Amphotericin B

Hypokalemia

Monitor potassium levels frequently

Digitalis glycosides

Digitalis toxicity

Hypokalemia

Monitor potassium levels frequently

Growth hormone

Ineffective

-

Potassium-depleting diuretics

Hypokalemia

Monitor potassium levels frequently

Vaccines from live attenuated viruses

Severe generalized infections

-

Table 4: Effects of Glucocorticoids on Blood Levels of Other Drugs (20)

PREDICTING GLUCOCORTICOID-INDUCED HPA AXIS SUPPRESSION

Several predictors of glucocorticoid-induced HPA axis suppression have been discussed, the major of which are the following:

Kind of Steroid Used and GC Potency

As shown in Table 1 long acting preparations have a longer tissue life which induces a chronic state of tissue hypercortisolism, making HPA axis suppression more likely. Thus, hydrocortisone and cortisone acetate are the least potent and, therefore, least suppressive agents. Prednisone, prednisolone, methylprednisolone and triamcinolone are moderately suppressive, and dexamethasone suppresses ACTH the longest.

Systemic Versus Compartmental Therapy

Systemic GC therapy, particularly parenterally, is more likely to suppress the HPA axis. However, other routes of administration such as inhalation, topical, intra-ocular cause HPA axis suppression as well as other systemic AEs and this depends on the systemic bioavailability of the drug (19, 48, 49, 95, 114, 123).

Daily Therapy

There is evidence that patients are at lower risk for adrenal insufficiency if they can take glucocorticoids on alternate days from the outset or if they can convert to alternate-day therapy before the HPA axis is suppressed (21, 129).

Split Doses and Night Doses

Administering GCs in several different doses during the day imposes a greater risk for HPA axis suppression. In the same way, evening doses of glucocorticoids tend to suppress the normal early morning surge of ACTH secretion, resulting in greater adrenal suppression. Whenever possible, it is better to treat patients with a single morning dose. Once-a-day dosing is usually feasible for intermediate or long acting GCs e.g. prednisone, triamcinolone and dexamethasone. The short-acting hydrocortisone and cortisone acetate are usually given twice a day, at waking and around 5 PM. To mimic normal diurnal cortisol rhythms, the morning dose is two thirds, and the afternoon dose one third of the total daily dose (19, 130, 131).

Duration and Cumulative Dose of Glucocorticoid Treatment

Although traditionally the duration of glucocorticoid therapy and the cumulative dose of glucocorticoid received have been considered as predictive of the likelihood of HPA axis suppression, several studies suggest that they only roughly predict HPA axis suppression (132-134). Adrenal insufficiency is extremely rare in patients treated for 1 week or less (135, 136). Nevertheless, with a so called "short-term" 14 day course of systemic GCs, generally considered safe, in patients with acute exacerbation of chronic obstructive pulmonary disease, suppression of the HPA axis has been defined (47).

Cushingoid Features

Patients with Cushing's syndrome symptoms due to GC therapy are more likely to have a suppressed HPA axis and adrenal atrophy (19).

It has been suggested that the best predictor of HPA axis suppression is the patient's current glucocorticoid dosage. A strong correlation has been found between prednisone maintenance doses above 5 mg/d and a subnormal ACTH-stimulation test result (137). Finally, it can be assumed that patients who are more likely to develop HPA axis suppression are those who receive high doses (>20-30mg prednisolone or equivalent) of systemic GCs for long periods (>3weeks) and those who appear to have Cushingoid features. As the HPA axis function in patients treated with synthetic GCs cannot be reliably estimated from the above parameters several tests are commonly used in order to assess the axis' recovery.

WEANING PATIENTS FROM GLUCOCORTICOID THERAPY

Besides their multiple therapeutic uses, GC withdrawal is indicated when their use is no longer recommended as the maximum therapeutic benefit has been obtained or when significant side effects appear and become uncontrollable, such as GC induced psychosis, diabetes mellitus, severe hypertension, and incapacitating osteoporosis. The goal of a successful GC withdrawal regimen can be described as the rapid transition from a state of tissue hypercortisolism to a state of total exogenous GC deprivation without resurgence of the underlying disease and without adrenal insufficiency or any other GC dependency. Although there are no consensus documents, several tapering regimens have been published so far. In clinical practice, the majority of physicians develop their own withdrawal regimens. The common point is that GC withdrawal should never be abrupt (19).

A systematic review published in 2002 found 9 randomized, controlled clinical trials, 7 of which investigated bronchial asthma and chronic obstructive pulmonary disease, which compared different GC tapering regimens. According to this review there was no significant difference between rapid or slow tapering, regarding the diseases' exacerbation and relapse rates, suggesting that prolonged withdrawal may not be necessary for a better outcome of the underlying disease. However, the same review highlighted the uncertainty about the safety and efficacy of GC withdrawal in many chronic diseases, emphasizing the need for further research in this area (131).

In general, patients taking any steroid dose for less than 2 weeks are not likely to develop HPA axis suppression and can stop therapy suddenly without tapering. The possible exception to this is the patient who receives frequent "short" steroid courses e.g. in asthma. Where there has been chronic therapy, the objective is to rapidly reduce the therapeutic dose to a physiological level (equivalent to 7.5mg/d prednisolone) e.g. by reducing 2.5mg every 3-4 days over a few weeks, and then proceed with slower withdrawal in order to permit the HPA axis to recover (19, 21).

As far as patients with underlying disease are concerned it is recommended that all available clinical, biochemical and laboratory data on the activity status of the disease be collected in order to easily identify signs of recurrence. In such a case prescribed doses should be increased (19).

After the initial reduction to physiological levels, doses should be reduced by 1mg/d of prednisolone or equivalent every 2-4 weeks depending upon patient's general condition, until the medication is discontinued. Alternatively, after the initial reduction to 5-7.5mg of prednisolone, the clinician can switch the patient to HC 20mg/d and reduce by 2.5mg/d every week until the dose of 10mg/d is achieved. After 2-3 months on the same dose, the HPA axis function should be assessed through a Corticotropin (ACTH-Synachten) test or through an Insulin Tolerance test (ITT). A pass response to these tests indicates adequate function of the axis and GCs can be safely withdrawn. If the axis has not fully recovered, treatment should be continued and the axis function should be reassessed (21).

Other tapering regimens have been published some of them dealing with switching the patient to an alternate dosage of GC before discontinuation (138).

Irrespectively of the tapering regimen used, if GC withdrawal syndrome, adrenal insufficiency's symptomatology, or exacerbation of the underlying disease appears, the dose being given at the time should be elevated or maintained for a longer period of time. Moreover, in the absence of evidence of HPA axis full recovery in patients who have been treated with GCs for prolonged periods, supplementation equivalent to 100-150mg of HC is recommended during situations of severe stress such as major surgery, fractures, severe systemic infections, major burns, etc.

Finally, it has become obvious, that all patients treated long-term with GCs should be treated in a similar fashion to patients with chronic ACTH deficiency, thus, they should be instructed to carry some type of identification (worn around the neck or wrist or carried as a card) (19, 21).

ACUTE ADRENAL CRISIS

Full HPA axis recovery after cessation of GC therapy may take as long as 1 year or more (11, 139). Abrupt cessation of glucocorticoid treatment or quick tapering can precipitate an acute adrenal insufficiency crisis. The main symptoms range from anorexia, fatigue, nausea, vomiting, dyspnea, fever, arthralgia, myalgia, and orthostatic hypotension to dizziness, fainting, and circulatory collapse. Hypoglycemia is occasionally observed in children and very thin adult individuals. The diagnosis is a medical emergency, and treatment should be immediate administration of fluids, electrolytes, glucose, and parenteral glucocorticoids.

GLUCOCORTICOID WITHDRAWAL SYNDROME (GWS)

Chronic administration of high doses of GCs and also other hormones such as estrogens, progestins, androgens and growth hormone induce varying degrees of tolerance, resulting in a progressively decreased response to the effect of the drug, followed by dependence and rarely "addiction". Traditionally, the term "Endocrine Withdrawal Syndromes" has been used to describe symptoms and signs of specific hormone deficiency after discontinuation of hormonal therapy or removal of an endocrine gland. However, discontinuation of hormonal therapy frequently results in a mixed picture of two different syndromes: a typical hormone deficiency syndrome and a generic withdrawal syndrome. Four aspects of GCs withdrawal after cessation of pharmacological high-dose therapy are important: 1) relapse of the underlying disease for which the drug was prescribed 2) HPA axis suppression which can persist for a long time 3) psychological dependence 4) a non-specific withdrawal syndrome despite normal HPA axis function and even while patients are receiving physiological replacement doses of GCs (140, 141).

Amatruda et al. first defined the steroid withdrawal syndrome as a symptom complex resembling true adrenal insufficiency, with nonspecific symptoms like weakness, nausea, and arthralgias, occurring in patients who have finished a dosage reduction of glucocorticoid therapy and who respond normally to HPA axis testing (142). Thus, after cessation of GC therapy patients may develop anorexia, nausea, emesis, weight loss, fatigue, myalgias, arthralgias, weakness, headache, abdominal pain, lethargy, postural hypotension, fever, skin desquamation, tachycardia, emotional lability, and even delirium, and psychotic states even if the response of the HPA axis to stimuli has returned to normal (140). Children and adolescents may experience signs and symptoms of GWS even when GCs are still being administered in supraphysiological doses (19). Biochemical evidence related to the GWS includes hypercalcemia and hyperphosphatemia (140).

The GWS has been considered a withdrawal reaction due to established physical dependence on supraphysiological GC levels (140). It has also been described as a state of relative GC resistance in these patients, effectively rendering them hypoadrenal (141). The mechanisms responsible for GWS have not been fully elucidated. Nevertheless, several mediators should be considered and include CRH, vasopressin, POMC, several cytokines such as IL-1β, IL-6, TNF-α, prostaglandins such as E2, I2, phospholipase A2 and also alterations of the noradrenergic and dopaminergic systems (19, 140).

The severity of GWS depends on the genetics and developmental history of the patient, on his environment, and on the phase and degree of dependence the patient has reached (140). The syndrome is self-limited with a median duration of 10 months. Its management should include a temporary increase in the dose of GCs followed by gradual, slow tapering to a maintenance dose (141).

BIOCHEMICAL DIAGNOSIS OF ADRENAL INSUFFICIENCY

Glucocorticoid treatment may not suppress the HPA axis at all, or it may cause central suppression and adrenal gland atrophy of varying degrees. Several endocrine tests have been used to define progression of glucocorticoid-induced adrenal insufficiency. The insulin tolerance test and the metyrapone test have been employed in the diagnosis of adrenal suppression and are quite sensitive, however, the risks involved with both tests do not justify their use when a rapid ACTH stimulation test can distinguish clinically significant adrenal suppression.

To evaluate the adequacy of hypothalamic-pituitary-adrenal axis recovery, the rapid Synachten (or high-dose ACTH stimulation test) is mostly used. An intravenous bolus of 250 ug of corticotropin 1-24 is administered and cortisol is measured after 30 or 60 minutes or both. A plasma cortisol concentration > 18 - 20 μg/ dL at these times indicates adequate recovery of the hypothalamic-pituitary-adrenal axis (139).

The low-dose Synachten test (1ug or 500 ng ACTH(1-24)/1.73 m2) is also being used for the assessment of the HPA axis after prolonged use of GC medication (143-145). It is unclear if the low-dose test is superior to the high-dose test for the detection of secondary adrenal insufficiency. Some studies have shown that the low-dose Synachten test is more sensitive in detecting partial secondary adrenal insufficiency (as can occur in chronic use of GCs), which is not detected by the standard high-dose test because the latter provides a supraphysiologic stimulus able to stimulate a partially damaged adrenal (146-149). A meta-analysis of 28 studies evaluated the utility of the high and low-dose ACTH test. At a specificity of 95% the sensitivity of the high-dose test for primary adrenal insufficiency was 97%, greater than that for secondary adrenal insufficiency (57%). The sensitivities for secondary adrenal insufficiency were similar between the high-dose (57%) and the low-dose Synachten test (61%) (150). In contrast, a review of the literature published between 1965 and 2007 suggests that the low-dose test is the best test currently available for establishing the diagnosis of secondary AI (151). Further studies are needed to establish if the low-dose Synachten test is preferable for the diagnosis of secondary AI.

The Corticotropin Releasing Hormone (CRH) test can also be used in patients taking GC treatment for prolonged periods, as it can assess both the ACTH and cortisol responses and can distinguish between secondary and tertiary adrenal insufficiency (133, 152).

The Dexamethasone Suppression Test has been shown to predict the later development of an impaired adrenal function after a 14-day course of prednisone in healthy volunteers and this information may allow a more targeted approach for the patients after cessation of steroid therapy (153).

FUTURE PERSPECTIVES ABOUT GLUCOCORTICOID THERAPY

Although hydrocortisone (HC) is the most commonly used regimen for replacement in patients with primary and secondary adrenal insufficiency, it is evident that this conventional therapy cannot provide the physiological rhythm of cortisol release. Moreover, with current replacement therapy, the majority of patients with adrenal insufficiency report impaired health-related quality of life, early morning fatigue, socioeconomic health problems and, finally, increased mortality (154). Circadian infusions of HC delivered by a programmable pump can mimic the normal rhythm of cortisol secretion and improve biochemical control and quality of life in patients with adrenal insufficiency and congenital adrenal hyperplasia. Because such infusions are not a practical solution, new formulations of oral HC, which mimic cortisol physiology have been evaluated. A dual-release hydrocortisone tablet with an immediate-release outer layer covering a sustained-release core, has been used in patients with Addison’s disease showing improvements in cardiovascular risk factors, including body weight, hemoglobin A1C and blood pressure, as well as a significant improvement in fatigue (154-156). In the long-term, this once-daily formulation was well-tolerated with a small number of adverse effects (157). Another modified-release multi-particulate hydrocortisone capsule formulation has been developed recently (158). This formulation was well tolerated and very effective in controlling disease biomarkers of congenital adrenal hyperplasia, such as androstenedione and 17-hydroxyprogesterone, with a lower hydrocortisone dose equivalency (154).

Apart from their use for hormonal replacement, the clinical success of synthetic GCs as anti-inflammatory agents is largely attributed to their ability to reduce the expression of proinflammatory genes, via activation of the GR and the concomitant inhibition of the activity of proinflammatory transcription factors, including NF-κB and AP-1, through a mechanism called trans-repression. On the other hand, the appearance of their AEs mainly arise from their ability to activate, after induction of the GR, target genes involved in the metabolism of sugar, protein, fat, muscle and bone via a mechanism called trans-activation (159, 160). There is a plethora of recent work dealing with the characteristics of novel selective GR ligands with equal efficacy and improved side-effects profiles, in other words ligands that show an improved therapeutic index (159-162). These efforts have resulted in a number of different terminologies: Selective GR modulators, selective GR agonists, gene-selective compounds, dissociated compounds, etc. (161, 163), which have been developed and are still being developed mainly focusing on the trans-repression mechanism and stimulating the side-effect pathway to a lesser extent, at least in specific tissues. Nevertheless, the likelihood of finding a compound that actually separates all activated genes from all repressed genes is highly unlikely mainly because the transactivation vs trans-repression characteristics are highly cell-type and gene specific. Moreover, it is also unclear whether such a compound would be truly desirable, as upregulation of anti-inflammatory genes may also play a role in the treatment of many diseases (159-161). In addition, many non-steroidal dissociated GR modulators, some of which do not support trans-activation, have shown promising benefit to side-effect ratios (e.g. ZK216348, CpdA) (159).

Considering the complexity of pathways regulated by GR, it is clearly too naive to assume that an ideal exogenous GR modulator only eliciting the beneficial anti-inflammatory effects without any trace of side-effects will ever be found. Complementing genome-wide gene profiling studies and transcription factor/DNA binding patterns on various target tissues at once will become an adamant strategy for the future (159). However, recent reports of Selective GR modulators provide fertile ground for additional efforts and it is obvious that any progress in this area would be a major benefit for thousands of patients receiving GC therapy (161).

Huber AM, Ward LM. The impact of underlying disease on fracture risk and bone mineral density in children with rheumatic disorders: A review of current literature. Semin Arthritis Rheum. 2016; 46(1):49-63.

ABSTRACT

Infections of the hypothalamic-pituitary region are rare lesions, accounting for less than 1% of all pituitary lesions. The clinical diagnosis of these infections can be difficult due to nonspecific nature of the disease (in many patients without symptoms of infection) and may be misdiagnosed as other pituitary lesions. The risk factors for infections of the hypothalamic-pituitary region are meningitis, paranasal sinusitis, head surgery, and immunocompromised host (diabetes mellitus, Cushing’s syndrome, HIV infections, solid organ transplantation, malignancy). Infections can develop in a normal pituitary gland or in pre-existing pituitary lesions (adenoma, Rathke´s cleft cyst, craniopharyngioma). There are several modes of dissemination of the infection to the hypothalamic-pituitary region: hematogenous, iatrogenic (after neurosurgical procedures), and spread from paranasal or nasal cavity (through venous channels of the sphenoid bone). Hypothalamic-pituitary infections most commonly present with visual disturbances and headache, in some cases with fever and leukocytosis. A significant proportion of patients develop hypothalamic-pituitary dysfunction during the acute phase of the disease or months and years after successful antimicrobial therapy. Diagnosis can be challenging and the hypothalamic-pituitary infection with formation of abscess or granuloma may be misdiagnosed as a pituitary tumor. Transsphenoid drainage followed by antibiotics, antimycotics or anti-tuberculous drugs are usually efficient in successful treatment of these patients. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

INTRODUCTION

Infections of the hypothalamic-pituitary region are rare and commonly described in case reports or small case series. These infections include: bacterial infections (pituitary abscess), tuberculosis, fungal, viral, and parasitic infections (Table 1). An infection in the hypothalamic-pituitary region may present as a sella/suprasellar mass and may be misinterpreted as a pituitary tumor. Also, these infections may cause hypopituitarism and be misdiagnosed as post-encephalitic syndrome (1-3).

Infections of the hypothalamic-pituitary region may be primary (without an identifiable source) or secondary in origin (3, 4). The more common is a primary pituitary infection, which occurs in previously healthy normal pituitary glands. Secondary pituitary infections occur in patients with a pre-existing lesion in the pituitary region (pituitary adenoma, Rathke´s cleft cyst, craniopharyngioma).

There are several sources of infections in the hypothalamic-pituitary region (Table 2). Dissemination from the sphenoid sinus to the pituitary is possible by direct contact and through shared venous drainage.

Infections in the hypothalamic-pituitary region are rare and several predisposing factors have been identified (2) (Table 3).

Table 3 – Predisposing Factors for Hypothalamic-Pituitary Infections

· Diabetes mellitus

· Tuberculosis

· Solid organ transplantation (renal, liver, etc.)

· Human immunodeficiency virus (HIV) infection

· Non-Hodgkin lymphoma

· Chemotherapy

· Cushing´s syndrome

· Previous pituitary surgery

· Immunosuppressive therapy

Infections of the hypothalamic-pituitary region may present with neurological signs and symptoms and signs of neuroendocrine dysfunction (Table 4).

Table 4 – Clinical Features of Hypothalamic-Pituitary Infections

NEUROLOGICAL SYMPTOMS

ENDOCRINE DYSFUNCTION

Headache

Hyponatremia

Visual disturbances

Hypopituitarism

Cranial neuropathy (III, IV, VI)

Hypogonadotropic hypogonadism

Hyperprolactinemia

Central diabetes insipidus

HYPOTHALAMIC-PITUITARY BACTERIAL INFECTIONS

Pituitary Abscess

Pituitary abscesses are rare pituitary lesions accounting for less than 1% of all pituitary lesions. The first case of a pituitary abscess was described in 1848 and since then it has been mostly described in case reports or small series. In two-third of patients, pituitary abscesses occur in previously healthy normal glands (5). In other patients, there is a preexisting lesion in the pituitary region, such as a pituitary adenoma, Rathke´s cleft cyst, or craniopharyngioma (4). The infection can be caused by hematogenous dissemination or by direct extension from surrounding structures (meningitis, sphenoid sinusitis, cavernous sinus thrombophlebitis) (Table 2). Pituitary surgery and immunocompromised condition are also risk factors for pituitary abscesses (Table 3).

According to the clinical presentation and duration of the disease, pituitary abscesses can be acute, subacute (the disease course less than 1 month), or chronic (disease course longer than 1 month) (6). Infective manifestations (fever, leukocytosis, meningism) have been reported in patients with acute and subacute pituitary abscesses, while chronic pituitary abscesses have a more indolent course.

The diagnosis of this potentially life-threatening disease is based on intraoperative detection of pus and postoperative histopathological analysis. Clinically, pituitary abscesses usually present with neurological signs and symptoms (headache, visual disturbances), signs of neuroendocrine dysfunction (anterior hypopituitarism, diabetes insipidus) and signs and symptoms related to infections (fever, leukocytosis) (4, 5). Compared to patients with a pituitary adenoma who rarely have neuroendocrine dysfunction, most patients with pituitary abscesses have hypopituitarism (5, 6). The largest case series of pituitary abscesses (66 cases) reported anterior pituitary hypopituitarism in 81.8% of patients, while diabetes insipidus was diagnosed in 47.9% of patients (5). Nine percent of patients (9.3%) had isolated hypogonadism, 3.7% had isolated ACTH deficiency, 1.8% had isolated hypothyroidism, and 1.8% had combined hypogonadism and ACTH deficiency (5). The possible source of the pituitary infection was found in 14 out of 66 patients (sepsis, sinusitis, pulmonary tuberculosis) (5).

On MRI, pituitary abscesses present as a sella masses, hypointense or isointense on T1-weighted imaging, hyperintense or isointense on T2-weighed imaging, with typical rim enhancement after gadolinium injection, mimicking apoplexy of the pituitary adenoma or other cystic sella lesions (5-9; Fig. 1). Diffusion-weighted imaging (DWI) sequences of pituitary abscesses often demonstrate high signal intensity with a reduction in the apparent diffusion coefficient, different from necrotic brain tumors (10).

The majority of patients are treated with transsphenoidal surgery, rarely with a transcranial approach (5). Intraoperatively, pus is found in the sella (11, 12). In patients with secondary pituitary abscesses, the sphenoid sinus is the most common site of extrasellar invasion (4).

On histopathological analysis, there is evidence of acute or chronic inflammation, while Gram staining and bacterial cultures in some cases may identify the infecting pathogen. In most cases, the etiological agents cannot be isolated. In the largest study on pituitary abscesses, positive results on gram staining or bacterial cultures were found in only 19.7% of patients (5). The most prevalent organisms are Gram-positive cocci (Staphylococcus and Streptococcus) (4).

Patients with bacterial pituitary abscesses are treated with intravenous and oral antibiotics to prevent the recurrence of the pituitary abscesses, but in some cases, reoperation was required. In rare cases, central diabetes insipidus and hypopituitarism are reversible, occasionally followed by secondary empty sella (13). In most cases, neuroendocrine dysfunction and diabetes insipidus are irreversible findings (6).

Although pituitary abscesses are more indolent than other intracranial abscesses, secondary pituitary abscesses in patients with pituitary adenomas (not in Rathke´s cleft cyst) is associated with high mortality rate (26%) due to the dissemination of the infection or meningitis (4).

Hypopituitarism Caused By Treponema Pallidum Infection (Syphilis)

Syphilis is a well-recognized cause of hypopituitarism, with granulomatous hypophysitis (noncaseating giant cell granuloma), syphilitic gumma in sella region, or congenital syphilis causing hypothalamic-pituitary dysfunction. The first cases of hypopituitarism caused by syphilis were described almost 70 years ago, mostly in postmortem cases (14). The use of penicillin caused the decline in syphilis presentations and late complications, including congenital syphilis. Nowadays, the incidence of syphilis has been rising again and this sexually transmitted disease should be considered again in the differential diagnosis of neurological, psychiatric and endocrine cases (15). Spirochete Treponema Pallidumis also described as a cause of hypophysitis and pituitary gland enlargement with hypopituitarism, mostly in immunocompromised patients (HIV-infected patients) with syphilitic meningitis (16). Syphilis may cause a sella mass with suprasella extension mimicking a pituitary tumor and causing severe headache and hypopituitarism (17). The diagnosis is confirmed by positive treponemal antibody or by detection of Treponema Pallidumby immunohistochemistry or PCR on the resected pituitary. This disorder is treated with antibiotics.

Hypothalamic-Pituitary Dysfunction Following Bacterial CNS Infections

Hypothalamic-pituitary dysfunction is a well recognized complication of acute infectious diseases of the central nervous system (meningitis and encephalitis) and may occur in the acute phase or in the late stage of these diseases (1, 18, 19). The clinical spectrum of the neuroendocrine dysfunction may range from an isolated pituitary hormone deficiency to panhypopituitarism. Endocrine dysfunction in the acute phase of meningitis may return to normal after the acute period or be irreversible (19). The most common deficit is isolated GH deficiency diagnosed 6-48 months after the infection, reported at rate of 28.6% (18).

Hypopituitarism following acute viral or bacterial meningitis in children is not as common as in adulthood (20, 21). The GH neurosecretory dysfunction (low IGF1 with normal GH response in clonidine test) was found in 3 out of 37 children tested at least 6 monhs following the diagnosis of bacterial meningitis (21). There are rare case reports on hypopituitarism during acute meningitis caused by Streptococcus Group Bor sepsis caused by Salmonella enteritidisin a neonatal period (22, 23).

The pathophysiologal mechanism responsible for hypothalamic-pituitary dysfunction following acute meningitis is not fully understood. In some patients, anti-pituitary and anti-hypothalamus antibodies are detected (24). It is proposed that acute infection provokes an autoimmune process and may cause axonal injury with consequent neuroendocrine dysfunction (25).

Tolosa-Hunt syndrome is defined as an idiopathic granulomatous inflammation of the cavernous sinus with variable extension into the superior orbital fissure/orbital apex, usually unilateral. The diagnosis is made by exclusion other more common causes of cavernous sinus lesion (thrombosis, tumors, fungal infections, systemic granulomatous diseases-sarcoidosis, tuberculosis, Wegener´s granulomatosis) (26). In less than 5% of cases it can be bilateral, mimicking a pituitary adenoma in imaging studies (27). The etiology of Tolosa-Hunt syndrome is not fully understood. The disease is characterized by nonspecific granulomatous inflammation with infiltration of lymphocytes and plasmocytes. The patient present with severe unilateral orbital pain and ipsilateral ocular motor neuropathy. The paralysis of one or more cranial nerves passing through the cavernous sinus (III, IV, VI) develops with the orbital pain or after less than 2 weeks. The signs of infection (fever, leukocytosis) are usually present. The granulomatous inflammation develops within the cavernous sinus causing acute throbbing orbital pain and disordered eye movement. Brain MRI scan demonstrade the inflammation in the cavernous sinus, orbital apex, and rarely in the sella. MR venography of the brain is important to exclude cavernous sinus thrombosis. Treatment consists of high dose corticosteroids and antibiotics. Refractory and steroid-intolerant cases may be treated with immunosupressants (Metotrexate or Azathioprine) and gamma knife radiotherapy (28). Periorbital pain intensity is rapidly decreasing and resolving within 72h, while the resolution of ophthalmoplegia improves gradually and takes a longer time to resolve (several weeks) (29). If the patient is not responding to standard therapy, the biopsy of the lesion is neccesary to exclude other diseases, such as lymphoma.

Hypothalamic-Pituitary Tuberculosis

The incidence of tuberculosis is rising not only in developing countries, but also in developed countries. Extrapulmonary tuberculosis may affect the brain causing tuberculous meningitis and tuberculoma of the central nervous cases. Tuberculous meningitis has a tendency to affect basal parts of the brain from where it can spread to the sella region. In rare cases, CNS tuberculosis may present as tuberculous hypophysitis or sella/suprasella tuberculoma mimicking a pituitary adenoma or pituitary apoplexy (30-32). It may occur in the absence of systemic tuberculosis, but majority of patients have a past history of pulmonary tuberculosis or tuberculosis of other organs (spine). Tuberculosis may affect the hypothalamus, pituitary, paranasal sinuses (sphenoid sinus), or a tuberculoma may be located only in the pituitary stalk. Hypothalamic-pituitary dysfunction and diabetes insipidus during the acute phase or years after recovery from acute tuberculous meningitis suggests a more destructive and more extensive hypothalamic and pituitary damage compared to other causes of acute viral and bacterial meningitis.

A significant proportion of patients with a sella tuberculoma or tuberculous meningitis develop hypothalamic-pituitary dysfunction. In 18 cases of histologically proved sella tuberculoma (5 of them with past history of tuberculosis), 5 patients had hypopituitarism and 3 had hyperprolactinemia due to pituitary stalk compression (30).

In patients with tuberculous meningitis half of them developed neuroendocrine dysfunction: hyperprolactinemia (23-50% od patients), hypocorticism (13-43%), hypothyroidism (17-31%), hypogonadism (34%), SIADH (10%) (33, 34)during the acute phase. Multiple hormonal axes were effeted in 23.5% of patients (33, 34). In young adult patients who survived tuberculous meningitis in childhood and were tested several years after recovery, hypopituitarism was diagnosed in 20% of patients (35). This is a consequence of fibrosis, gliosis, and calcification in the hypothalamus and pituitary after recovery of active tuberculous brain infection. In rare cases, pituitary function recovered after successfull treatment with anti-tuberculous drugs (36).

The diagnosis of sella tuberculoma is a challenge, especially in cases with no systemic tuberculosis. The signs and symptoms are nonspecific: fever, neurological abnormalities (headache, visual disturbances) and neuroendocrine dysfunction (30, 37). Sella tuberculoma on MRI scans presents as thickening of the pituitary stalk or abnormal enhancement pattern of the sella lesion (38) (Fig. 2).

If the correct diagnosis is established and anti-tuberulous drugs are effective surgery is not indicated for tuberculous hypophysitis. With surgery the histological examination shows granulomas with central caseous necrosis surrounded by giant Langhans cells. In cases in whom Ziehl Neelsen staining for acid fast bacilli and the culture on Lowenstein-Jensen media are negative, PCR for detection of mycobacterial DNA in tissue or CSF may help.

HYPOTHALAMIC-PITUITARY FUNGAL INFECTIONS

Hypothalamic-pituitary fungal infection are extremely rare and occur usually in immunocompromised patients (diabetes mellitus, granulocytopenia, solid organ transplatation). There are only few case reports of Candida and Aspergillus sella abscesses and reviews of fungal sellar abscesses (39-44). Aspergillus is an ubiquiotous saprophitic fungus found in nasal mucosa of healthy persons and patients with chronic sinusitis. This fungus may cause CNS infection, such as meningitis, encephalitis, brain abscess, subdural abscess, pituitary absces, and mycotic arteritis (45, 46). Fungal sella abscesses have a nonspecific presentation, with neurological signs and symptoms (headache, visual disturbances) and hypothalamic-pituitary dysfunction. Sella MRI images are nonspecific, with a T1W hypointense or isointense mass with rim enhancement and may be misdiagnosed as a pituitary adenoma (Fig. 3). It is proposed that low signal on T2W images due to iron deposition may be a more specific sign of fungal abscess (42, 47; Fig. 4). Diagnosis of fungal pituitary abscess is made by histopathological finding (Groccot methenamine silver stain demonstrates septate fungal hyphae), cultivation, or PCR identification of fungus DNA. A combination of transsphenoidal drainage and antifungal therapy (liposomal Amphotericin B, itraconazole, voriconazole, caspofungin) can result in a good prognosis (39, 43, 44, 48). Endocrinopathies caused by fungal abscess have a low rate of recovery (43).

Fig. 4. Fungal infections in the sella: a) CT scan of the sinuses (axial view) shows a large sellar mass, erosion in sellar floor, propagation of the pathological process and opacification of the sinuses, and B) sellar MRI scan (coronal view) shows a giant hypointense lesion in the sellar region.

An unusual form of allergic fungal sinusitis which expands from the sphenoid sinus through a bone erosion to the sella in immunocompetent patient has been descibed (47)(Fig. 4). This patient had hyperprolactinemia (in the setting with no pituitary stalk compression), which resolved after sucessful transsphenoidal operation followed by anti-mycotics and corticosteroids (47). It is speculated that fungal glucans may directly stimulate glucan-specific receptors on somatomammotroph cells to stimulate prolactin secretion (49).

HYPOTHALAMIC-PITUITARY VIRAL INFECTIONS

Hypothalamic-pituitary dysfunction (hypopituitarism and cranial diabetes insipidus) may develop in the acute phase of viral infections of the CNS (meningitis and encephalitis) or in the late stage of these diseases (1, 18, 19). Infectious agents which cause CNS viral infections are listed in Table 5.

Table 5 – Infectious Agents Which Cause CNS Viral Infections

MENINGITIS

ENCEPHALITIS

Herpes virus

Tick-borne

Varicella

Herpes simplex

Enterovirus

Cytomegalovirus

Neuroborreliosis

The investigation of hypothalamic-pituitary function at least 6 month after recovery from mild-to-moderate menigitis/encephalitis showed that 21% patients developed isolated corticotroph deficiency, while other neuroendocrine abnormalities or diabetes insipidus were not found (1).

Hemorrhagic fever with renal syndrome (HFRS), caused by Hantaviruses in the Bunyaviridae family, is an endemic zoonotic disease transmitted by rodents. There are several serotypes of these RNA viruses causing systemic infection, milder form called nephropathia endemica (Puumala) or severe form (Dobrava, Belgrade). The disease is endemic in Europe (Balkans, Finland, Germany) and Asia (Korea), where several outbreaks have been recorded. Farmers and solders are exposed to the virus by inhalation of infected rodent urine, feces or saliva. Hantavirus infiltrates the vascular system causing increased capillary permeability, renal failure, thrombocytopenia, hemorrhage, fever, hypotension and shock.The mortality rate is 6.6%. Autopsy findings reported a slightly enlarged pituitary with ischemia/infarction, hemorrhage, and necrosis (50-52). Direct viral invasion was confirmed in the pituitary causing viral hypophysitis (52). Hypothalamic-pituitary dysfunction has been reported during the acute phase of the disease or after long-term follow-up (53-60). Milder form of HFRS infection caused by Puumala virus (nephropathia epidemica) is accompanied by a lower incidence of hypopituitarism (61). It is speculated that in some patients with no signs of hemorrhage in the sella, hantavirus may cause autoimmune hypophysitis and hypopituitarism (62).Sellar MRI imaging in hypopituitary patients reveals an edematous pituitary gland or increased signal intensity in the pituitary due to hemorrhage during the acute phase, while pituitary atrophy and secondary empty sella develops months and years after acute infection (59, 61, 62) (Fig 5). A retrospective study of 60 adults who had recovered from HFRS reported that 18% of patients developed hypopituitarism (63). Ten percent of patients had a single pituitary deficit (three GH, two gonadal and one adrenal), and 8.3% had multiple pituitary hormone deficiencies (63). In rare cases, HFRS may cause injury of the pituitary stalk and central diabetes inspidus with panhypopituitarism (60).

Also, cytomegalovirus, herpes simpex, varicella zoster, and enterovirus have been described in very rare cases of central diabetes insipidus, mainly in immunocompromised patients with encephalitis (such as HIV infection, Cushing´s syndrome, lymphoma or immunosuppresive therapy) (64-68). Direct cytomegalovirus invasion and reduction in the number of AVP and oxytocin cells were confirmed in the hypothalamus (65).

HYPOTHALAMIC-PITUITARY PARASITIC INFECTIONS

Toxoplasmosis is a worldwide zoonozis, caused by the protozoan parasite Toxoplasma gondii. This is one of the most common parasitic infection of warm-blooded animals and humans. Aproximately one-third of humans have been exposed to T. gondii, mostly with no serious diseases, except in immunocompromised patients (HIV) and congenital toxoplasmosis. Also, two cases of prolactinomas with T. gondii cysts among tumor cells were reported (69). Toxoplasmosis is the most common CNS infection in immunocompromised patients (patients with HIV infection) and may cause hypopituitarism, accompanied with focal neurological deficits, headache, fever (70, 71). The brain MRI shows lesions with significant enhancement of T2W images and peri-lesional edema, which may be misdiagnosed as intracranial metastasis. The diagnosis is based on brain biopsy with confirmed presence of T. gondiiby PCR. Infection with T. gondiiis treated with antimicrobial therapy and with hormone replacement therapy as needed.

ABSTRACT

Empty sella is a radiological finding of a flattened pituitary in a sellar space filled with cerebrospinal fluid. It may be primary or secondary consequent to various processes causing injury and shrinkage of the pituitary gland (postpartum hemorrhage, pituitary surgery, irradiation, apoplexy, infection, head trauma, hypophysitis, etc.). The mechanisms involved in the pathogenesis of the so called “primary empty sella” may range from continuously or intermittently increased intracranial pressure due to idiopathic benign intracranial hypertension, obesity, arterial hypertension, or multiple pregnancies in female patients with accompanying insufficiency of the sellar diaphragm and changes in pituitary gland volume (hyperplasia during pregnancy, lactation, menopause etc.). Primary empty sella can be an incidental radiological finding in an asymptomatic patient with preserved pituitary function. In symptomatic patients with the so called “empty sella syndrome” (headache, visual disturbances and hormonal dysfunction), the radiological finding of an empty sella is important in the differential diagnosis of other sellar lesions. Hypopituitarism, partial or complete, and hyperprolactinemia are not uncommon in these patients. The treatment of hypopituitarism and hyperprolactinemia is advocated in all patients with confirmatory results. In patients with the secondary empty sella, hypopituitarism is more common and more readily recognized due to damage caused by surgery, radiation therapy or various pathological causes. Rarely, empty sella can be associated with hormonal hypersecretion from an “invisible” micro adenoma producing prolactin, growth hormone (acromegaly) or ACTH (Cushing’s disease). A wide range of radiological findings in patients with secondary and primary empty sella coupled with clinical data (important hints from the history and data on endocrine function) are presented for further illustration of this topic. For complete coverage of this area and all areas of Endocrinology, visit www.endotext.org.

HISTORY

The term ‘empty sella’ was first used by Bush in 1951 (1) to describe a peculiar anatomical condition, observed in 40 of 788 human cadavers, particularly females, characterized by a sella turcica with an incomplete diaphragm sellae that forms only a small peripheral rim, with a pituitary gland not absent, but flattened in such a manner as to form a thin layer of tissue at the bottom of the sella turcica. Kaufman (2), in 1968, speculated that ‘…empty sella is a distinct anatomical and radiographic entity, function of an incompleteness of the diaphragma sellae and of the cerebrospinal fluid (CSF) pressure, normal or elevated’. The role of the normal fluctuations of CSF pressures and the effect of a superimposed prolonged increase in CSF pressure were related to the anatomic changes involving the bony wall of the empty sella.

DEFINITION, ETIOLOGY, AND PREVALENCE OF EMPTY SELLA

Empty sella is defined as herniation of subarachnoid space into the sella turcica (arachnoidocele). It is a term for the radiological finding of “empty sellar space” on magnetic resonance imaging (MRI) and computerized tomography (CT) with a flattened pituitary and elongated stalk. It can be partial if less than 50% of sellar space is filled with cerebro-spinal fluid (CSF), or complete if CSF fills more than 50% of space in the sella and gland thickness is less than 2mm (3,4).

Regarding its etiology, it can be primary if there is no pathological process in the sellar region preceding the pituitary damage or secondary if it is consequent to a specific pathological process. Primary empty sella (PES) can be an incidental finding or may arise during imaging for headache, endocrine disorders, neurological symptoms, visual disturbances, abnormal sella turcica radiograph, and other reasons.

Primary empty sella (PES) can be caused by intracranial hypertension and/or insufficiency of the sellar diaphragm in subjects with no previous history of pituitary disease. Insufficiency of the sellar diaphragm, a deflection of dura matter separating the suprasellar cistern from the pituitary fossa, allows unobstructed pulsatile movements of CSF from chiasmatic cistern causing flattening of the pituitary to the sellar floor. In extreme cases bone erosion of the sellar floor and CSF leak (rhinorrhea) may occur, increasing the risk of meningitis. Partial or complete absence of the sellar diaphragm has been demonstrated in patients with PES.

Intracranial pressure can be intermittently increased due to obesity, sleep apnea, arterial hypertension, pregnancy, and labor. Intracranial hypertension may be idiopathic or associated with other intracranial processes such as tumors, venous thrombosis, infections, or malformations. Idiopathic intracranial hypertension (IIH) or “pseudo-tumor cerebri” is a rare condition affecting 1 in 100,000 persons. It can be due to impaired CSF absorption, increased CSF secretion and/or increased capillary permeability (5). Impaired CSF dynamics and absorption have been found in up to 77% and 84% of patients with PES, respectively (6), The prevalence of PES is very high in patients with IIH ranging from 70-94% (4).

Changes in the pituitary gland volume may also be involved in the pathogenesis of empty sella syndrome including hyperplasia during pregnancy and lactation and pituitary involution after menopause accounting for the significantly higher prevalence of this condition in female patients (female to male ratio 5:1).

Factors involved in the pathogenesis of primary empty sella are shown in Figure 1.

Secondary empty sella is more common and is related to various pathological processes of the sellar region. Among many causes pituitary tumor shrinkage occurring after medical treatment, surgery, radiotherapy, and apoplexy of a pituitary adenoma are frequent causes of secondary empty sella. Likewise, postpartum pituitary necrosis, pituitary infection, hypophysitis, and traumatic brain injury may lead to pituitary atrophy. The diagnosis of secondary empty sella is more difficult if there is no known underlying pathology involving the pituitary gland. In these cases, the sella is normal in size, and the function of the flattened pituitary gland may or may not be compromised. Such is the case in congenital causes of hypopituitarism both acquired and genetic, presenting with a hypoplastic pituitary gland and ectopic posterior lobe. Large intracranial tumors such as slow-growing meningiomas can also cause increased intracranial pressure and secondary empty sella in a significant number of patients. Pituitary MRI images of patients with secondary and primary empty sella are presented in the section dedicated to radiological appearance of an empty sella (Fig. 2-6). Associated risk factors for primary and secondary empty sella are shown in Table 1.

The reported prevalence of empty sella depends on techniques used for detection. In autopsy studies empty sella has been found in up to 5.5-12% cases (1,2), On imaging the overall incidence has been estimated at 12% (4). The prevalence of PES is very high in patients with IIH.

Figure 1. Factors involved in pathogenesis of primary empty sella including the upper-sellar factors, incompetence or incomplete formation of the sellar diaphragm, and pituitary factors associated with the variation in the pituitary volume. Modified from Bioscientifica Ltd., Chiloiro S et al, European Journal of Endocrinology (2017) 177, R275–R285

RADIOLOGICAL APPEARANCE OF EMPTY SELLA

Most commonly an empty sella is incidentally discovered during MRI or CT imaging or during evaluation for headache, endocrine, neurological or visual disturbances. Less commonly it is observed after additional imaging for abnormal sella turcica radiographs. Chronic intracranial hypertension can lead to sellar remodeling and enlargement with thinning of the sellar floor and rarely rhinorrhea.

On typical presentation CSF filling is in continuity with overlying subarachnoid spaces and the residual pituitary gland is flattened against the sellar floor of enlarged bony sella with pituitary volume usually less than 611.21 mm3(7). The differential diagnosis with cystic lesions and congenital pituitary abnormalities may pose a challenge. The stalk is usually thinned and located in the midline. Asymmetry is a frequent sign of the secondary empty sella. In rare cases the chiasm can herniate into the sella in cases of both primary and secondary etiology. Indirect signs of intracranial hypertension may also be present such as flattening of the posterior sclera, prominent subarachnoid spaces along the optic nerves, vertical tortuosity of the optic nerve sheath complex, and increased width of the optic nerve sheaths (8).

Sagittal and coronal T1-weighted (T1W) contrast enhanced images and coronal T2-weighted (T2W) images are strongly indicated for MR studies because they show CSF within the sella. On FLAIR sequences the intrasellar fluid completely suppresses and it presents without restriction in DWI sequences. After contrast T1W images show normal enhancement of residual pituitary gland and the stalk in PES in contrast to scaring and distortion in SES.

In patients with congenital hypopituitarism an ectopic posterior pituitary, stalk duplication or absence may be present in combination with other midline defect (agenesis of corpus callosum, supraoptic dysplasia, etc.).

Figure 2. Sagittal T1W images of two patients with empty sella and Sheehan’s syndrome
Left Panel (sagittal T1W image without contrast) and Right (sagittal T1W image after contrast enhancement) represent the MRI appearance of empty sella in two patients with Sheehan’s syndrome. Both patients presented with hyponatremic coma due to unrecognized panhypopituitarism and infection 3 and 20 years after delivery complicated by postpartum hemorrhage.

Figure 5. Sagittal T1W showing small pituitary gland found at the bottom of sella, thin stalk and ectopic posterior lobe in a young adult with isolated childhood-onset growth hormone deficiency (congenital).

PRIMARY EMPTY SELLA (PES) AND EMPTY SELLA SYNDROME

Epidemiologically, this is associated with female sex (female to male ratio 5:1), multiple pregnancies, obesity, arterial hypertension and middle age. It may present with headaches, endocrine dysfunction, and visual disturbances due to pressure on the neighboring structures.

A typical clinical picture consists of headache and obesity. Women in the reproductive age may be affected by menstrual irregularities, galactorrhea and sterility. Man can develop gynecomastia and sexual disturbances. Primary empty sella due to the syndrome of increased intracranial pressure can also be associated with symptoms of intracranial hypertension.

Pathogenesis of Primary Empty Sella (PES)

Pregnancy may trigger the onset of PES. It is associated with pituitary hyperplasia and CSF hypertension especially in multiple pregnancies. PES has also been associated with CSF hypertension related to obesity and arterial hypertension. In the largest study with 175 patients, multiple pregnancies were reported in 58.3% women with PES, while obesity and arterial hypertension were recorded in 49.5% and 27.3% of patients (8). In patients with benign intracranial hypertension, empty sella is a common finding.

Endocrine Dysfunction in PES

Hyperprolactinemia, usually mild (less than 50 ng/ml), is present in approximately 10% of patients (8). It is often due to increased pressure of the CSF on the pituitary stalk and diminished dopamine inhibitory effect. Prolactin dynamics in PES may be influenced by gonadal status, intracranial pressure, neurotransmitters, and stalk integrity. Rarely, pituitary microadenomas causing acromegaly and Cushing’s disease may be associated with empty sella.

The prevalence of hypopituitarism in patients with PES is variable. In a study by Guitelman et al. it was found in 28% of patients (9). Panhypopituitarism was present in 40% of these patients, while partial or isolated hormone deficiencies were diagnosed in 60% of hypopituitary patients (9). The most prevalent pituitary deficiency was growth hormone deficiency.

In a pooled meta-analysis, which included 4 studies, the frequency of hypopituitarism was 52% (10). Multiple pituitary hormone deficiencies were present in 30%, isolated in 21% of patients with PES. Growth hormone and the gonadotropins were most common isolated insufficiencies (10).

Hormonal assessment is advocated in all patients with ES. In case of borderline results or suspected isolated or partial insufficiency stimulatory tests are recommended if clinically relevant for hormone replacement.

Other symptoms in patients with ES include: headache, visual and neurological disturbances. In patients with intracranial hypertension these symptoms are more common.

Neurological and Ophthalmic Dysfunction in PES

Headache is present in approximately 80% (3,6). In 20% of patients it may be accompanied by visual disturbances, even papilledema in intracranial hypertension (3,6).

Visual disturbances including worsening of visual acuity, blurred vision, diplopia, defects of oculomotor nerve, and optical neuritis were also reported in patients with PES. In case of benign intracranial hypertension ophthalmic echography and computerized visual field with evoked potentials should be performed in consultation with ophthalmologists. In case of chiasmal herniation into the empty sella with acute visual deterioration, new neurosurgical techniques of chiasmal transsphenoidal elevation are available (11).

TREATMENT

In patients with increased idiopathic intracranial pressure osmotic diuretics or acetazolamide (Diamox) are advocated. Weight loss may be efficient in obese and overweight patients especially if accompanied by sleep apnea. Neurosurgical techniques may be indicated for rhinorrhea and some symptomatic secondary causes of empty sella syndrome with increased intracranial pressure and acute visual disturbances. If diagnosed hypopituitarism should be replaced following the current recommendations (12) and hyperprolactinemia treated with dopamine agonists.

CONCLUSION

Primary empty sella can be heterogeneous in origin and presentations range from an asymptomatic incidental radiological finding to endocrine and neuro-ophthalmological manifestations. Female sex, multiple pregnancies, obesity, and arterial hypertension are associated risk factors as well as the syndrome of benign intracranial hypertension. Secondary empty sella is caused by various pathological processes resulting in shrinkage of the pituitary gland. Routine hormonal status assessment and regular follow-up are indicated in all patients since the prevalence of pituitary dysfunction is significant.

ABSTRACT

Radiation treatment is used for patients with secreting and non-secreting pituitary adenomas, with residual pituitary adenomas, or recurrent pituitary adenomas with the aim to achieve long term disease control. Radiotherapy is an integral component of managment of other tumors in the sellar region (craniopharyngiomas) and for certain types of cancers and lymphomas. Pituitary hormone deficiencies are the commonest late complication of radiotherapy, which usually occur after several years. The development of hormone deficiencies with time varies in the published literature. Predictors for the development of hypopituitarism are the dose of radiation and the age at time of treatment. Different pituitary axes appear to have different radiosensitivity with the somatotrophic axis being the most sensitive. Long-term endocrine evaluations are recommended in patients after cranial radiotherapy to identify new pituitary hormone deficiencies and introduce appropriate hormone replacement therapy. Clinicalevaluation, baseline pituitary hormone assessment, and dynamic testing for growth hormone and adrenocorticotropic hormone (ACTH) deficiency should begin one year after cranial radiotherapy. Compared with conventional radiotherapy, advanced radiation technologies(stereotactic radiosurgery, cyber knife, fractionated stereotactic radiotherapy, proton beam therapy) are presumed to have the ability to deliver radiation to the tumor with remarkable precision minimizing its effects on healthy tissues. Results from larger series with longer length of follow-up are needed to help clinicians identify who will benefit most from advanced radiation techniques. For complete coverage of this area and all areas of Endocrinology, visit www.endotext.org.

INTRODUCTION

In the past few decades survival of patients with brain tumors, including malignant tumors has improved greatly. However, these patients tend to develop acute and late complications of tumor treatment, which includes cranial irradiation.

The rationale for radiotherapy is to achieve excellent long-term tumor control after partial surgical excision and published 10-year tumor control rates are reported to be high. The following diseases are treated with radiotherapy: pituitary adenomas or other sellar tumors not derived from pituitary tissue (craniopharyngioma, meningioma, germinoma), brain cancers, head and neck tumors, and acute lymphoblastic leukemia (ALL) (Table 1)

Following radiotherapy, the side effects of radiotherapy may be acute toxicity (within weeks of completion of therapy) and late toxicity which occur years after treatment. The risk of toxicity depends on the total radiation dose. Doses are divided into fractions and the duration of cranial radiotherapy varies from one or a few days in short courses to several weeks of daily radiations in long courses. Higher doses (up to 60Gy) are used for pituitary tumors, non-pituitary brain tumors, head and neck tumors (nasopharyngeal cancer, rhabdomyosarcoma) and skull-base tumors, while lower doses are used in patients with ALL and total body irradiation before bone marrow transplantation (1-14).

Conventional radiotherapy has been used for the longest period of time. Conventional radiotherapy is administered by a linear accelerator, with a total dose of 40-45Gy, in at least 20 sessions. A single beam of high-energy radiation is focused onto a small treatment area, but the radiation also includes healthy surrounding tissue. Technical advances in radiotherapy refer to high precision treatment (stereotactic) and they include radiosurgery (gamma knife), robotic arm mounted linear accelerator (cyber knife), and proton beam therapy(Table 2) (15). Initial data suggest that the radiation-associated endocrine dysfunctions may be reduced with these new radiation techniques. However, further clinical studies are needed to better define the consequences of these new radiation methods.

Table 2. Radiation Techniques

Type

Characteristics

Number of sessions

CONVENTIONAL

The fractionation allows normal tissue to recover, while tumorous tissue is destroyed

INCIDENCE OF RADIATION-INDUCEDNEUROENDOCRINE DYSFUNCTION

A number of studies reported very different incidences of radiation-induced hypopituitarism, central precocious puberty, or hyperprolactinemia, depending on indications for radiotherapy, radiation technique, radiation dose, and duration of follow-up.

Pituitary Adenomas

The incidence rate of new onset hypopituitarism after conventional radiotherapy in patients with recurrent or residual functioning or nonfunctioning pituitary adenoma reaches 30-100% after follow-up of 10 years (26-29). According to the data from one of the largest cohorts of 4110 patients with adult-onset growth hormone (GH) deficiency (Pfizer International Metabolic Database, KIMS), 36% of patients with isolated GH deficiency and 37% of patients with multiple pituitary hormone deficiencies had a history of cranial radiotherapy (30).

Brain Tumors Distant From the Hypothalamus and Pituitary

Studies with shorter follow-up showed that 41% of patients irradiated for brain tumors distant from the hypothalamus and pituitary region developed hypopituitarism, 16% with isolated pituitary hormone deficiency and 25% with multiple pituitary hormone deficiencies (31). The largest study with long follow-up (median 8 years) showed a higher prevalence of pituitary dysfunction (88.8%) after cranial radiotherapy for adult-onset non-pituitary brain tumors (32). GH deficiency was the most frequent neuroendocrine abnormality (86.9% of patients), followed by gonadotrophin deficiency (34.6%), ACTH deficiency (23.4%) and TSH deficiency (11.2%). Hyperprolactinemia was reported in 15% of patients. Single pituitary axis dysfunction was reported in 41.1% of patients, while multiple pituitary hormone deficits were present in 47.7% of patients (32).

A meta-analysis of 18 studies with a total of 813 patients showed that approximately two thirds of all adults previously treated with cranial radiotherapy for an intracranial tumor or nasopharyngeal cancer developed some degree of hypopituitarism (33). Growth hormone deficiency was the most prevalent (45%), followed by gonadotropin deficiency (30%), TSH deficiency (25%) and ACTH deficiency (22%).

Childhood-Onset Brain Tumors

In the largest cohort of childhood-onset brain tumors (Childhood Cancer Survivor Study, CCSS), 43% of 1607 children who survived their disease for 5 or more years developed one or more anterior pituitary hormone deficiencies (34). Cranial radiotherapy in childhood often affects growth causing growth retardation and affects sexual development causing early or delayed puberty. A retrospective clinical study reported the prevalence of hypopituitarism in a large cohort of 748 adult survivors in the USA treated with cranial radiotherapy in childhood (CCSS), among them 72% with a leukemia diagnosis (9). After a long duration of follow-up (mean 27.3 years, range 10-47 years), the prevalence of GH deficiency was 46.5%, gonadotropin deficiency 10.8%, TSH deficiency in 7.5% and ACTH deficiency in 4%. Recently published guidelines of the Endocrine Society addresses the diagnosis and treatment of hypothalamic-pituitary and growth disorders encountered in childhood cancer survivors (35).

Cranial irradiation causes irreversible and progressive damage to the hypothalamic-pituitary region. There are several pathophysiological mechanisms of the radiation-induced hypopituitarism including direct hypothalamic neuronal and vascular injury, with secondary pituitary atrophy being the most common mechanism. Female acute lymphoblastic leukemia (ALL) survivors treated with cranial radiotherapy had smaller hypothalamic volume (measured on T1-weighed MRI images), compared to gender matched controls (36).

The integrity of the microstructure of the hypothalamus can be examined in vivousing the MRI technique diffusion tensor imaging (DTI), based on the direction and degree of the diffusion of water molecules. This MRI technique shows brain tissue microstructure alterations and provides information about brain white matter organization by assessing the restriction of randomly moving water molecules. Recently, this new technique of in vivobrain damage investigation was used in cranially irradiated patients (ALL and childhood craniopharyngioma survivors) (37). Important microstructure alterations in the hypothalamus were detected in ALL survivors, with worse alterations in overweight survivors compared to survivors with normal weight. These microstructure alterations suggest demyelinaton and axonal loss the hypothalamus and were not found in childhood onset craniopharyngioma survivors without hypothalamic involvement (37).

Direct pituitary damage may also occur, as it is the case in patients after stereotactic radiosurgery for pituitary adenomas. The third mechanism of radiation induced hypothalamic dysfuntion is the alteration of the neurotransmitters from other brain regions which regulate hypothalamic function (38-40). The posterior pituitary gland is less sensitive to radiation injury.

NEUROENDOCRINE DYSFUNCTION AFTER CRANIAL IRRADIATION

The incidence and severity of radiation-induced neuroendocrine dysfunction depends on radiation dose, radiation schedule, and duration of follow-up.

Radiation Dose

The severity and frequency of pituitary hormone deficiencies, hyperprolactinema, or central precocious puberty as a complication of cranial radiotherapy correlates with the total radiation dose (Table 4).

The somatotroph axis is the most vulnerable and isolated growth hormone deficiency (GHD) may occur with a low radiation dose of 18 Gy (41, 42). If the radiation dose is less than 30 Gy, isolated GHD is present in 30% of patients (4, 26, 43). The incidence of GHD increases to 45-100% of patients if the radiation dose is 30-50Gy (33, 43-46).

If radiation dose is less than 18 Gy, central precocious puberty is a potential complication (with lower effective dose in girls compared with boys), while TSH and ACTH deficiencies are uncommon (13, 33, 47). A large retrospective study reported that the prevalence of central precocious puberty following the treatment of 80 patients with pediatric cancer and CNS tumors was 15.2% overall (29.2% for tumors in the hypothalamic-pituitary region and 6.6% for other CNS tumors) (48).

With the increase of radiation dose, GHD is followed by other pituitary hormone deficiencies: gonadotropin deficiency (30% of patients), TSH deficiency (6-25% of patients) and ACTH deficiency (22% of patients) (33).

Radiotherapy Schedule

The severity of neuroendocrine dysfunction after cranial radiotherapy also depends on the radiotherapy schedule. If the total radiation dose is administered over a short period it will induce more hypothalamic-pituitary damage than if the same dose is administered over a longer period.

Follow-Up Period

The incidence of radiation-induced hypopituitarism correlate also with the time elapsed since treatment (28, 29). Hormone deficits accumulate throughout the follow-up period, with the majority of hormone deficits developing during the first 5 years postradiotherapy. In a large study of the effect of cranial radiotherapy in patients with nonpituitary brain tumors, the incidence of all pituitary deficiencies almost doubled between years 2 and 7 of follow-up (32).

NEW RADIATION TECHNIQUES AND HYPOTHALAMIC-PITUITARY DYSFUNCTION

New stereotactic radiation techniques (stereotactic radiosurgery with a Leksell gamma knife, a stereotactic linear accelerator, a Cyber Knife, or proton beam therapy) have been developed with the aim to improve effectiveness, to irradiate less normal tissue, and to reduce toxic effects (16). The stereotactic radiation techniques involve photon energy from multiple 60Cobalt radiation sources (gamma knife) or a modified linear accelerator (LINAC). It can be delivered as a single fraction stereotactic radiosurgery or as a fractionated stereotactic radiotherapy. Stereotactic radiosurgery is a single dose radiation technique at doses of 16-25 Gy used in patients with small and medium-sized pituitary adenoma at least 2-4mm from the optic chiasm, whereas fractionated stereotactic radiotherapy is used in patients with large (>2.5-3cm) pituitary adenoma, frequently involving the optic chiasm (49).

Gamma Knife Stereotactic Radiosurgery

Gamma knife stereotactic radiosurgery delivers in a single session a highly collimated dose of ionizing radiation (60Cobalt) conformed to the shape of the target and sparing normal tissue, in contrast to conventional radiotherapy, which covers the tumor and the surrounding structures with a fractionated dose gradient of radiotoxicity between target cells and normal tissue. As already mentioned, gamma knife stereotactic radiosurgery is usually used in patients with relatively small tumors not in close proximity of the optic apparatus (at least 2-4mm away from the optic chiasm). The patient wears a rigid metal helmet fixed on the scull. The radiation is delivered in one session and the dose delivered to the tumor margin are higher for functioning pituitary adenomas (18-35 Gy), compared with nonfunctioning pitutiary adenomas (10-20Gy) (49). The studies on long-term follow-up results of gamma knife stereotactic radiosurgery in patients with pituitary adenoma reported radiation-induced hypopituitarism in up to 50% of patients (24, 25, 50-57). A study with long-term endocrine and radiographic follow-up of patients with acromegaly or Cushing’s disease treated with gamma knife radiosurgery showed more than a half of patients (58.3%) had new pituitary deficiencies after the median time of 61 months (range 12-160) (58). GH deficiency was the most common deficiency (28.3%) and the rate of hypopituitarism gradually increased with time of follow up (10% at 3 years, 21.7% after 5 years and 53.3% at 10 years of follow-up) (58). Gamma knife radiosurgery is also an option in patients with medically and surgically refractory prolactinomas, in whom hypopituitarism was reported in 30.3% of patients after median follow-up od 42 months (range 6-207.9) (55).

Some predictors of hypopituitarism following gamma knife stereotactic radiosurgery have been identified and include margin dose to the tumor, suprasellar extension, the radiation dose to the distal infundibulum (maximum safe dose of 17 Gy), cavernous sinus invasion of the tumor, and the amount of healthy tissue within the high dose region (52, 54, 58-60). Data referring to the development of hypopituitarism related to gamma knife radiosurgery shows that keeping the mean radiation dose to the pituitary under 15 Gy and the dose to the distal infundibulum under 17 Gy may prevent the development of radiation-induced hypopituitarism (59).

Fractionated Stereotactic Radiotherapy

Stereotactic radiosurgery is a convenient radiotherapeutic aprroach for patients with small either secreting or nonfunctioning pituitary tumors, but caution should be used in patients with moderate or large-sized tumors (>3 cm) in close proximity to critical structures (optic chiasm and brainstem). For these patients, fractionated stereotactic radiotherapy (FSRT) may be a safer treatment option because of advantages of dose fractionation. This therapy is used at doses of 45-54Gy delivered in 25-30 daily fractions in patients with pituitary adenomas. In a study on the efficacy and safety of FRST in patients with large and invasive nonfunctioning pituitary tumors, the incidence of new anterior pituitary deficits was 40% at 5 years and 72% at 10 years, while no other radiation-induced complications occurred (61). In patients with tumors located near the optic structures, hypofractionated radiotherapy may be used, because of lower toxicity for the optic nerves compared with single-dose radiosurgery. Recently published meta-analysis with more than 600 patients with pituitary adenomas showed that both stereotactic radiosurgery and fractionated stereotactic radiotherapy have comparable efficacy and safety (62).

Proton Radiotherapy

Proton radiotherapy is the conformal technique used for certain types of cancer and lymphomas, with precise delivery of radiation to a tumor and decreased radiation dose to normal brain because of lower entrance dose and elimination of exit dose compared with photon beams. Less normal brain is irradiated at low or intermediate doses and this could decrease the risk of late effects of radiation, such as endocrinopathy, second malignancy, or neurocognitive deficits. Initial studies suggest lower rates of endocrine complications in children treated with proton radiation for medulloblastoma and low-grade glioma, with increased sparing of normal tissues (63, 64). The comparison between photon radiotherapy and proton radiotherapy for medulloblastoma showed that newer proton radiotherapy may reduce the risk of some radiation-associated endocrine complications (hypothyroidism and gonadotropin deficiency), but not all complications (the incidence of GH and ACTH deficiency, or precocious puberty was not changed) (64). It seems that proton conformal radiotherapy has advantages over conventional photon therapy for children with gliomas. Depending on the tumor location, it can spare the hypothalamic-pituitary axis. There was only 1 patient with endocrinopathy in the 14 irradiated children in the low (radiation dose less than 12 Gy) or intermediate endocrine risk groups (radiation dose 12-40Gy) (63).

The most recently published study on the effects of proton radiotherapy in a large group of 189 pediatric and young adult patients treated for brain tumors showed that the rate of any pituitary hormone deficiency at four years was 48.8% (65).The incidence of hormone deficiencies was strongly associated with the dose of radiation and the age at time of treatment, with children being especially sensitive.

In the future the late consequences of new radiation techniques should be more completely defined.

Recently, recommendations for screening for hypopituitarism after cranial radiotherapy were suggested (13, 35, 66). According to this approach, clinical evaluation, baseline pituitary hormone assessment, and dynamic testing for GH and ACTH deficiency should begin one year after cranial radiotherapy (Table 5). Clinical examination of children (including linear growth and pubertal staging) should be done every 6 to 12 months until final height is attained, and then yearly thereafter (13, 35). In patients at risk for central precocious puberty, pubertal development should be monitored every 6 months until age 9 years in girls and 10 years in boys (13).

If results of the assessment are normal, reassessment should be done every 2-4 years until at least 10 years following radiation. GH testing should be done only in patients who are good candidates for GH replacement therapy (keeping in mind the safety in underlying malignancy). It is also recommended to perform an endocrine assessment at 1 year after radiotherapy in patients treated for nonpituitary intracranial neoplasms, since they also may develop hypothalamic-pituitary dysfunctions (67).

Table 5. Screening for Hypothalamic-Pituitary Dysfunction

DYSFUNCTION

Clinical data

Basal analysis

Dynamic test

GH deficiency

Growth velocity (children)

IGF-I

ITT, glucagon, clonidine (children)

FSH/LH deficiency

Pubertal staging

FSH, LH, estradiol (female), testosterone (male)

GnRH

TSH deficiency

Clinical examination

TSH, FT4

TRH

ACTH deficiency

Clinical examination

cortisol

ITT, Synacthen

Hyperprolactinemia

PRL

Precocious puberty

Pubertal stage

FSH, LH, estradiol (female), testosterone (male)

Somatotroph Axis

Two stimulation tests for estimating GH secretion are required in the case of isolated GHD, while in patients with multiple pituitary hormone deficiencies there is no need for formal testing to establish a diagnosis of GH deficiency.Interpretation of results for the GH stimulatory tests following cranial radiation may be complicated because of the different mechanisms governing GH release during the gold standard, the insulin tolerance test (ITT), and other tests (arginine+GHRH and GHRH+GHRP-6 test in the past). In some cases the results of different GH stimulatory tests may be discordant (41; 68, 69). The hypothalamus is more sensitive to radiation-induced injury compared with pituitary. Provocative tests which directly stimulate the somatotrophs (GHRH) may give false negative results in the early years after radiotherapy (70). Failing to pass the hypoglycemia test (ITT) is more common after radiation than to other stimulatory tests, but may not necessarily reflect GH deficiency (71-74). It has been suggested that lower radiation doses (<40 Gy) predominantly cause hypothalamic damage with GHRH deficiency and subsequent somatotrope atrophy. In cases with robust response to ITT it is suggested to repeat screening at four years, while in cases with borderline response to this test, it should be repeated at two years (66).

IGF-1 levels may be useful in screening for severe GH deficiency in children and adults (35). However, in childhood cancer survivors exposed to cranial radiotherapy, it is recommended against relying solely on serum IGF-I levels to make the diagnosis of GH deficiency (35).

The hypothalamic-pituitary-adrenal axis and hypothalamic-pituitary-thyroid axis are more radioresistant than the GH and gonadotropin axes. Corticotroph deficiency is defined as low morning serum cortisol (normal range for morning serum cortisol, 7– 25 mg/dl; for evening serum cortisol, 2–14 mg/dl) and a normal or low serum ACTH level. Thyrotroph deficiency is based on a low free T4 with normal or decreased TSH. ACTH and TSH deficiency may occur after a large dose of cranial radiation (>50 Gy) used for nasopharyngeal cancer and skull base tumor, in 30-60% of patients after long-term follow-up (4, 26, 28, 29, 33, 43, 46). Central hypocorticism and hypothyroidism may be subclinical and diagnosed by stimulatory tests (ITT, glucagon, Synacthen test and TRH test).

Second CNS Tumor

The systematic review of 21 studies in children and adults who received cranial radiation for prophylactic or therapeutic purposes showed a 7-10-fold increase in subsequent CNS tumors in children, with a latency period ranging from 5.5 to 30 years (glioma developed 5-10 years and meningioma around 15 years after radiation) (21). Additional investigation is needed on the risk of radiation-induced secondary tumors in adults, because some studies showed no increased risk, while other studies reported a higher risk for secondary CNS tumors with a latency period from 5 to 34 years (21). A large study that included 8917 patients from the Pfizer International Metabolic Database (KIMS) reported an increased incidence for de novo brain tumors in patients treated for pituitary/sellar lesions (22). The risk of developing a malignant brain tumor increased by 2-4-fold and meningioma by 1.6-fold with every 10 years of younger age at radiotherapy, irrespectively of the type of radiotherapy (conventional vs stereotactic) (22).

CONCLUSION

Hypothalamic-pituitary dysfunction is among the most common late effect of cranial radiotherapy.Radiation causes irreversible and progressive damage to the hypothalamic-pituitary region. The pathophysiology of the radiation-induced damage includes direct neuronal and vascular injury and fibrosis. The incidence and severity of hypopituitarism correlate with the total radiation dose delivered to the hypothalamic-pituitary region, the fraction size, the time between fractions, and the duration of follow-up. Periodical life-long endocrine assesmment is recommended in all long-term survivors of childhood or adulthood tumors who were treated with cranial radiotherapy or with total body irradiation. Further analysis of new radiation techniques and long-term hypothalamic-pituitary dysfunctions are needed.

CLINICAL RECOGNITION

Adrenocortical cancer (ACC) is a rare disease with an annual incidence of 0.7-2 cases per million per year and two distinct age distribution peaks, the first occurring in early adulthood and the second between 40-50 years with women being more often affected (55-60%). Although the great majority of ACCs are of sporadic origin, they can also develop as part of familial diseases the most common being the Beckwith-Wiedeman syndrome, the Li-Fraumeni syndrome, the Lynch syndrome, the multiple endocrine neoplasia (MEN) 1, and familial adenomatous polyposis (FAP) (Table 1). In recent years several multi-center studies have shed light on the pathogenesis of ACC but ‘multi-omic’ studies reveal that only a minority of ACC cases harbour pathogenic driver mutations.

Table 1. Clinical and Genetic Features of Familial Syndromes Associated with ACC

The clinical features of sporadic ACCs are due to hormone hypersecretion and/or tumor mass and spread to surrounding or distant tissues. An increasing number of cases (≈ 10-15%) are increasingly been diagnosed within the group of incidentally discovered adrenal masses (incidentalomas). However, the likelihood of an adrenal incidentaloma being an ACC is rather low. Approximately 50-60% of ACCs exhibit evidence of hormonal hypersecretion, usually that of combined glucocorticoid and androgen secretion (Table 2). Nearly 30-40% of patients with primary ACC present with a mass syndrome as abdominal or dorsal pain, a palpable mass, fever of unknown origin, signs of inferior vena cava (IVC) compression, and signs of left-sided portal hypertension. Rarely, complications as hemorrhage or tumor rupture may also develop. Lately the number of patients that are identified while being investigated for an adrenal incidentaloma is rapidly increasing.

Table 2. Signs and Symptoms of ACC and Recommended Testing for Confirmation of Hypersecretory Syndromes

Symptoms/Signs

Hormonal testing (ENSAT 2005)

Hypercortisolism

Centripetal fat distribution

Skin thinning – striae

Muscle wasting – myopathy

Osteoporosis

Increased blood pressure (BP)

Diabetes Mellitus

Psychiatric disturbance

Gonadal dysfunction

Overnight dexamethasone

suppression test (1mg)

24-hour free cortisol

Basal ACTH (plasma)

Basal cortisol (serum)

[for diagnosis minimum 3 out of 4 tests)

Androgen hypersecretion

Hirsutism

Menstrual irregularity – infertility

Virilization (baldness, deepening of the voice, clitoris hypertrophy)

DHEA-S

Androstendione

Testosterone

17-OH-progesterone

Mineralocorticoid hypersecretion

Mineralocorticoid excess with increased BP, hypokalemia

Potassium (serum)

Aldosterone to renin ratio

Estrogen hypersecretion

Gynecomastia (men)

Menorrhagia (post-menopausal women)

17β-estradiol

Non-hypersecretory syndrome

PATHOPHYSIOLOGY

Although studies of hereditary neoplasia syndromes have revealed various chromosomal abnormalities related to ACC development the precise genetic alterations involved are still unknown. The Wnt/β-catenin constitutive activation and insulin growth factor 2 (IGF2 overexpression) are the most important implicated genetic pathways. Germline TP53 mutations and dysregulation of the Gap 2/mitosis transition and the insulin-like growth factor 1 receptor (IGF1R) signalling have also been described. Steroidogenic factor 1 (SF1) plays an important role in adrenal development and is frequently overexpressed in ACC.

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS

A palpable mass causing abdominal pain in the presence of the inferior vena cava syndrome IVC syndrome is highly suggestive of an ACC. This is substantiated further by the presence of symptoms/signs of combined hormonal secretion (cortisol and androgens), virilizing or rarely feminizing signs confirmed with the use of specific endocrine testing (Table 2). As the majority of ACCs are relatively large (size > 8cm, weight >100g) at diagnosis, specific imaging features are used to distinguish them from other adrenal lesions. If adrenal imaging indicates an indeterminate mass other parameters should be considered including tumor size > 4 cm, combined cortisol/androgen hormone excess, rapidly developing symptoms and/ rapid tumor growth and/or young age (e.g. < 40 years) that might point to an ACC.

Other adrenal lesions that need to be considered in the differential diagnosis are myelolipomas, adrenal hemorrhage, lymphoma, adrenal cysts, metastases, and mainly adrenal adenomas, the majority of which have distinctive imaging features. There is no role for biopsy in a patient who is considered suitable for surgery of the adrenal mass.

Computerized Tomography (CT) scanning of the adrenals is the major tool showing a unilateral non-homogenous mass, >5cm in diameter, with irregular margins, necrosis, and occasionally calcifications. Due to the low-fat content X-Ray density is high (>20 Hounsfield Units, HU); in a recent series of 51 ACC none had a density of less than 13 HU. The presence of enlarged aorto-caval lymph nodes, local invasion, or metastatic spread are highly suggestive of ACC. For 3-6 cm size lesions, measuring X-Ray tumoral density before and after contrast administration and estimating washout percentage can be helpful; less than 50% after 15 minutes, is associated with >90% specificity. On Magnetic Resonance Imaging (MRI), ACC appears hypo or isointense to the liver on T1-weighted images, and using gadolinium enhancement and chemical shift techniques the diagnostic accuracy obtained is 85-100%. Recently Positron Emission Tomography (PET-scan) with 18F-fluoro-2deoxy-D-glucose (18FDG) has been proposed as possibly the best second-line test to assess indeterminate masses by unenhanced CT exhibiting 95-100% sensitivity and 91-94% specificity that increases further when fused with CT imaging. Furthermore, 18FDG-PET can also be used as a staging procedure identifying metastatic adrenal disease missed by conventional imaging studies including CT of the chest. With the proper implementation of imaging studies there is no need for adrenal biopsy.

HISTOPATHOLOGICAL DIAGNOSIS

The expression of SF1 is a valid marker to document the adrenal origin (distinction of primary adrenocortical tumors and non-adrenocortical tumors) with a sensitivity of 98% and a specificity of 100%. If this marker is not available, a combination of other markers can be used which should include inhibin-alpha, melan-A, and calretinin. ENSAT has shown that KI67 is the most powerful prognostic marker in both localized and advanced ACC and that higher Ki67 levels are consistently associated with worse prognosis. Weiss system, based on a combination of 9 histological criteria that can be applied on hematoxylin and eosin-stained slides, for the distinction of benign and malignant adrenocortical tumors is the best validated score to distinguish adenomas from ACC although with high inter-observer variability.

PROGNOSIS

As survival depends on stage at presentation several different classification histopathological systems have evolved with the reported 5-year survival using the ENSAT system being 82% for stage I, 61% for stage II, 50% for stage III, and 13% for stage IV (Table 3). Tumor size remains an excellent predictor of malignancy as tumors > 6cm have a 25% chance of being malignant compared to 2% of those with a size < 4cm. As there is no single distinctive histopathological feature indicative of malignancy the Weiss score has been used with a score >3 being suggestive of malignancy and recently ki67 labelling index >10%.

Table 3. Staging system for adrenocortical carcinomas proposed by the International Union against cancer (WHO 2004) and the European Network for the study of adrenal tumors (ENSAT).

The median overall survival (OS) of all ACC patients is about 3-4 years. The prognosis is, however, heterogeneous. Complete surgical resection provides the only means of cure. In addition to radical surgery, disease stage, proliferative activity/tumor grade, and cortisol excess are independent prognostic parameters. Five-year survival rate is 60-80% for tumors confined to the adrenal space, 35-50% for locally advanced disease, and significantly lower in case of metastatic disease ranging from 0% to 28%. European Network for the Study of Adrenal Tumors (ENSAT) staging is considered slightly superior to the Union for International Cancer Control (UICC) staging. Additionally, the association between hypercortisolism and mortality was consistent. As Ki67 has been shown to be related with prognosis in both localized and advanced ACC threshold levels of 10% and 20% have been considered for discriminating low from high Ki67 labelling index; however, it is not clear whether any single significant threshold can be determined. Patients with stage I-III disease treated with surgical resection had significantly better median OS (63 vs. 8 months; p= 0.001). In stage IV disease, better median OS occurred in patients treated with surgery (19 vs. 6 months; p=0.001), and postsurgical radiation (29 vs 10 months; p=0.001) or chemotherapy (22 vs. 13 months; p= 0.004). Overall survival varied with increasing age, higher comorbidity index, grade, and stage of ACC at presentation. There was improved survival with surgical resection of the primary tumor, irrespective of disease stage; post-surgical chemotherapy or radiation was of benefit only in stage IV disease.

THERAPY

The management of patients with ACC requires a multidisciplinary approach with initial complete surgical resection in limited disease (stage I, II and occasionally III). Mitotane (1,1-dichloro-2(o-chlorophenyl)-2-(p-chlorophenyl) ethane [o,p’DDD]) is the only currently available adrenolytic medication achieving an overall response of approximately 30%.

Surgery

The aim of surgery is to achieve a complete margin-negative (R0) resection as patients with an R0 resection have a 5-year survival rate of 40-50% compared to the < 1year survival of those with incomplete resection. Patients with stage III tumors and positive lymph nodes can have a 10-year OS rate of up to 40% after complete resection. When a preoperative diagnosis or high level of suspicion of ACC exists, open surgical oncological resection is recommended as locoregional lymph removal might improve diagnostic accuracy and therapeutic outcome. However, the wide range of reported lymph node involvement in ACC (from 4 to 73%) implies that regional lymphadenectomy is neither formally performed by all surgeons nor accurately assessed or reported by all pathologists. Laparoscopic adrenalectomy should be considered for tumors with size up to 6 cm without any evidence of local invasion. Routine locoregional lymphadenectomy should be performed with adrenalectomy for highly suspected or proven ACC and it should include (as a minimum) the peri-adrenal and renal hilum nodes.

Preservation of the tumor capsule is essential whereas involvement of the IVC or renal vein with tumor thrombus is not a contraindication for surgery. However, even following an apparently complete surgical resection, 50-80% of patients develop locoregional or metastatic recurrence. Although such patients may be candidates for aggressive surgical resection, routine debulking is not recommended except for control of hormonal hypersecretion. Ablative therapies particularly targeting hepatic disease are used to decrease tumor load and the hypersecretory syndromes. Individualized treatment decisions are made in cases of tumors with extension into large vessels based on multidisciplinary surgical team. Such tumors should not be regarded ‘un-resectable’ until reviewed in an expert center.

Mitotane

Mitotane has traditionally been used for ACCs obtaining a partial or complete response in 33% of cases mainly by metabolic transformation within the tumor and through oxidative damage. Besides its cytotoxic adrenal action mitotane also inhibits steroidogenesis.

Adjuvant mitotane treatment is proposed in those patients without macroscopic residual tumor after surgery but who have a perceived high risk of recurrence (stage III, KI-67%>10%). However, for patients at low/moderate risk of recurrence (stage I-II, R0 resection, and Ki67 ≤ 10%) treatment with adjunct mitotane is still under investigation (results from ADIUVO trial are pending). When indicated mitotane should be initiated within six weeks and not later than 3 months. Adjuvant mitotane should be administrated for at least 2 years, but no longer than 5 years.

The tolerability of mitotane may be limited by its side effects mainly nausea, vomiting, neurological (ataxia, lethargy), hepatic and rarely hematological toxicity. Measurement of serum mitotane levels, targeting a range of 14-20 mg/l, seems to correlate with a therapeutic response while minimizing toxicity using variable dosing regimens. Mitotane causes hyperlipidemia and increased hepatic production of hormone binding globulins (cortisol, sex hormone, thyroid and vitamin D) increasing total hormone concentration while impairing free hormone bioavailability. The induction of hepatic P450-enzymes by mitotane induces the metabolism of steroid compounds requiring high dose glucocorticoid and mineralocorticoid replacement.

Hormonal excess causes significant morbidity in ACC patients. Although mitotane reduces steroidogenesis it has a slow onset of action necessitating the use of other adrenostatic medications (ketoconazole, metyrapone, aminoglutathemide, and etomidate). As adrenal insufficiency may occur close supervision is required to titrate adrenal hormonal replacement therapy.

Cytotoxic Chemotherapy

Although cisplatin containing regimens have shown some responses most studies lack power and comparisons between different regimens. The most encouraging results originate from the combinations of etoposide, doxorubicin and cisplatin with mitotane (EDP-M) achieving an overall response of 49% of 18 months duration (FIRMA-CT study). This regimen was equally effective as first line treatment or after failing of the combination of streptozotocin with mitotane and is the currently the preferred scheme. In patients who progress under mitotane monotherapy, EDP treatment is also recommended. The combination of gemcitabine with capecitabine is used for patients failing EDP- and for not responding patients targeted therapies with tyrosine kinase inhibitors (mainly sunitinib) could be used. Although initially promising treatment with IGF-1R antagonists did not prove to be efficacious suggesting that combination of therapies may be the way forward.

Radiation Therapy

Radiotherapy has a role in symptomatic metastatic disease particularly bone disease with positive responses in up to 50% - 90% of cancer patients.

Evolving Therapies

Targeting mTOR pathway alone using everolimus did not produce significant responses. An extended phase I study of the anti-IGF-1R monoclonal antibody cixutumumab with an mTOR inhibitor showed a partial but short-lived response. The use of the multikinase inhibitors sorafenib and sunitinib have also shown partial responses leading to a number of phase II studies whereas angiogenesis inhibitors have not been successful (http://www.clinicaltrials.gov). Other potential targets are antagonists of β-catenin and Wnt signaling pathway and SF-1 inverse agonists. The application of radionuclide therapy using 131I-metomidate has recently been explored. However, despite recent advances in dysregulated molecular pathways in ACCs, these findings have not yet been translated into meaningful clinical benefits. Lately immunotherapy (pembrolizumab) in phase II studies is under investigation.

FOLLOW-UP

Patients who have undergone an apparently curative resection should be followed up regularly using endocrine markers and abdominal imaging. After complete resection, radiological imaging every 3 months for 2 years and then every 3-6 months for a further 3 years is proposed. 18FDG-PET should be performed at regular intervals to detect recurrent disease at high risk patients. Patients on mitotane therapy should be regularly monitored measuring serum mitotane levels ensuring adequate replacement therapy. In case of recurrence not amenable to surgical excision patients should be enrolled in prospective clinical trials.

CLINICAL RECOGNITION

Adrenal suppression, a form of secondary adrenal insufficiency (SAI), is a common clinical problem most often due to sudden cessation of chronic exposure to exogenous glucocorticoid administration or, rarely, after correction of endogenous hypercortisolism. It results from the inability of suprahypothalamic and hypothalamic centers of the hypothalamic-pituitary-adrenal (HPA) axis to recover their function and can last from days to months or years, depending on the dose and duration of the exposure to the glucocorticoid and patient’s idiosyncrasy. Exogenous glucocorticoids cause decreased secretion of corticotropin-releasing hormone (CRH) and other adrenocorticotropic hormone (ACTH) secretagogues, such as arginine-vasopressin (AVP) and alter the function of higher brain centers that regulate their secretion. Recovery of adrenal function may take as long as 1 to 2 years. In cases of endogenous hypercortisolemia adrenal suppression develops after the removal of a functional adrenal tumor secreting cortisol, or following successful removal of ACTH-secreting pituitary adenoma or other sources of ectopic ACTH secretion. Interestingly, the period to recover from adrenal suppression after the removal of ACTH-secreting pituitary adenoma caused by prolonged suppression of normal corticotrophs may be a predictor of sustained remission.

Regarding the definitions of adrenal insufficiency (AI), it is a disorder characterized by impaired adrenocortical function and decreased production mainly of glucocorticoids. Primary AI (PAI) is characterized, in addition by decreased production of mineralocorticoids (MCs) and/or adrenal androgens that occur in the setting of diseases affecting the adrenal cortex. Secondary AI (SAI) arises in diseases or conditions affecting the pituitary gland and the secretion of ACTH, while the affected hypothalamus resulting in abnormal secretion of corticotropin-releasing hormone (CRH) and other ACTH secretagogues defines the tertiary form of AI (TAI).

As adrenal suppression refers to decreases of cortisol secretion from the adrenal zona fascicularis the function of zona glomerulosa remains normal. Thus, hyponatremia is the main electrolytic disturbance observed, while circulating plasma potassium, renin, and aldosterone concentrations are within the normal range.

A broad range of severity can be seen as a result of complete or partial HPA axis suppression and concomitant adrenal gland atrophy. The true prevalence of overt adrenal insufficiency (AI) is probably rare as glucocorticoid treatment is gradually tapered before complete discontinuation leaving enough time for HPA axis recovery. However, due to the lack of specific symptoms the exact prevalence of AI following glucocorticoid tapering may be under-reported. Two recent systematic reviews reported that the percentage of patients with AI ranged from 0% to 100%, with a median (IQR) = 37.4% (13–63%), while when the studies were stratified by administration route, the percentages of patients with AI ranged from 4.2% for nasal administration (95% confidence interval [CI], 0.5–28.9) to 52.2% for intra-articular administration (95% CI, 40.5– 63.6); by disease, from 6.8% for asthma with inhalation glucocorticoids only (95% CI, 3.8 –12.0) to 60.0% for hematological malignancies (95% CI, 38.0 –78.6); by the dose from 2.4% (95% CI, 0.6 –9.3) (low dose) to 21.5% (95% CI, 12.0 –35.5) (high dose); by treatment duration from 1.4% (95% CI, 0.3–7.4) (less than 28 days) to 27.4% (95% CI, 17.7–39.8) (more than 1 year) in asthma patients.

The main symptoms of glucocorticoid insufficiency range from anorexia, fatigue, nausea, vomiting, dyspnea, fever, arthralgias, myalgias, and orthostatic hypotension to dizziness, fainting, and circulatory collapse. Hypoglycemia is occasionally observed in children and very thin adult individuals. Since 1-3% of adults worldwide are under long-term glucocorticoid therapy (Table 1), the awareness for adrenal suppression and the associated risk for glucocorticoid deficiency, as well as the appropriate treatment, are important clinical issues.

Many synthetic compounds with glucocorticoid activity have been developed in an attempt to maximize the beneficial and minimize the deleterious effects of glucocorticoids. The clinical efficacy of synthetic glucocorticoids depends on their pharmacokinetic, pharmacodynamic and molecular properties, which in turn determine the duration and intensity of glucocorticoid effects. According to their potency synthetic glucocorticoids are subdivided into short-, intermediate-, or long-acting. Treatment modifying factors, such as the age of the patient and the nature and severity of the underlying disease also influence synthetic glucocorticoid effects, duration, and doses administered.

The British National Formulary and the National Institute for Health and Care Excellence Clinical Knowledge Summary, both advise gradual glucocorticoid withdrawal in cases of patients that have received more than 40 mg prednisolone (or equivalent) daily for longer than one week; repeated glucocorticoid doses in the evening; glucocorticoids for more than three weeks; a short course of glucocorticoids within one year of stopping long-term glucocorticoid therapy; or have other risk factors for adrenal suppression.

PATHOPHYSIOLOGY

Supraphysiologic doses of glucocorticoids given even in small doses and/or for only a few days may result in considerable suppression of the HPA axis by decreasing CRH synthesis and secretion. The trophic and ACTH-releasing effects of CRH on pituitary corticotrophs are attenuated and the synthesis of propiomelanocortin (POMC), ACTH, and other peptides, are substantially decreased. In the absence of ACTH, the adrenal cortex temporarily loses the ability to produce cortisol, and when treatment with glucocorticoids is abruptly stopped transient glucocorticoid insufficiency ensues. It has been reported that the suppression of the HPA axis induced by exogenous glucocorticoids may persist for 6 to 12 months or rarely even longer, after treatment is withdrawn.

DIAGNOSIS and DIFFERENTIAL DIAGNOSIS

To support the diagnosis of adrenal suppression, several predictors of glucocorticoid-induced HPA axis hypofunction have been suggested the best being the duration and dosage of exogenous glucocorticoid administration (Table 2,3). A strong correlation has been found between prednisone maintenance doses above 5mg/d and a subnormal ACTH-stimulation test result. Hence, patients who are more likely to develop HPA axis suppression are those receiving high doses of glucocorticoids (>20-30mg hydrocortisone or equivalent) (Table 4) for a period longer than 3 weeks and patients who have developed overt Cushingoid features. In addition, the timing of drug administration may affect the degree of adrenal suppression. Thus, prednisolone in a dose of 5mg given at night before bedtime and 2.5mg in the morning will produce more marked HPA axis suppression compared to 2.5mg at night and 5mg in the morning. Higher evening doses block early morning ACTH surge whereas tissues sensitivity to glucocorticoids is increased in the evening and early night hours.

Table 2: Predictors of Glucocorticoid-Induced HPA Axis Suppression

Predictor

Etiology/Risk of HPA Suppression

Type of steroid and potency

Long-acting GCs lead to longer tissue life and longer suppression

Route of administration

Systemic GC therapy (parenterally): increased risk

Timing
of administration

Decreased risk in alternate days scheme (from outset or converted before suppression);

Table 4: Glucocorticoid Equivalent Dose Compared to Cortisol

equivalent dose (mg)

Short-acting, low potency

Cortisol

20

Cortisone

25

Intermediate-potency

Prednisolone

5-7.5

Methylprednisolone

4

Long-acting, high potency

Dexamethasone

0.75

Clinical awareness is crucial to identify patients with impending adrenal crisis. It is important to consider all patients with unexplained symptoms after glucocorticoid- withdrawal as candidates for possible AI and test them accordingly. An important feature that will raise suspicion of TAI (and SAI) besides drug history is the absence of skin pigmentation. Such patients have an intact renin-angiotensin-aldosterone system (RAAS) accounting for the differences in salt and water balance and clinical presentations compared to primary adrenal insufficiency.

Serum cortisol secretion at 08:00h if diagnostic tests are not feasible and until confirmatory testing is available can be considered a valuable screening method when AI is suspected. In patients with a low index of suspicion obtaining an 8AM cortisol and if the serum cortisol is > 15μg/dL, no further testing is needed. Similarly, a serum cortisol value <5 μg/dL suggests AI.

DIAGNOSTIC TESTS NEEDED TO DOCUMENT AI

Drug history and clinical features cannot be considered reliable tools for the evaluation of HPA axis function in patients treated with synthetic glucocorticoids. Several tests are commonly used in order to assess the degree of glucocorticoid-induced AI or HPA axis recovery (Table 5,6). Both the insulin tolerance test (ITT) and the metyrapone test have been employed as they are both highly sensitive. However, the risks involved with these tests do not justify their use compared to the rapid ACTH stimulation test or short synacthen test (SST) that can safely distinguish almost all cases of clinically significant adrenal suppression.

To evaluate the adequacy of HPA axis recovery, the SST is used to assess the capability of the adrenal cortex to respond to ACTH. However, because of the supraphysiologic ACTH levels achieved with the conventional SST (250 mcg of ACTH administered), if adrenal suppression is of recent onset, the adrenal gland may have not yet atrophied, and is still capable of responding to ACTH stimulation. In these cases, the low-dose SST (1 mcg of ACTH administered) has been proposed as an alternative as it results in lower plasma ACTH levels and thus less pronounced adrenal stimulation. It has recently been suggested that the low-dose SST is the best test to establish the diagnosis of SAI and TAI, whereas the high SST should be used for cases of primary AI. The use of salivary cortisol is also an effective alternative to serum cortisol when assessed in the high-dose ACTH test. Incremental cortisol response at the first SST was suggested as an important predictive factor of adrenal function recovery in SAI after exogenous glucocorticoid administration.

The CRH test can also be used in patients receiving glucocorticoids for prolonged periods, as it can assess both the ACTH and cortisol responses and can distinguish between SAI and TAI. In both conditions, cortisol concentrations are low at baseline and remain low after CRH administration. In patients with SAI, there is little or no ACTH response, whereas in patients with tertiary disease there is an exaggerated and prolonged response of ACTH, which is not followed by an appropriate cortisol response. On the contrary, patients with primary AI have high ACTH levels, which rise further following CRH while patients with hypothalamic disease show a steady rise in ACTH levels.

The prolonged ACTH stimulation test (depot or iv infusions 250µg cosyntropin over 8 hrs or over 24hrs) was suggested as a mean to differentiate between the different types of AI but is now rarely used in routine practice. In SAI or TAI, the adrenal glands display cortisol secretory capacity following prolonged stimulation with ACTH whereas in primary AI, they do not respond to ACTH being partially or completely destroyed.

In a recent systematic review of AI assessment after systemic glucocorticoid therapy, SST (conventional or low-dose) was the most frequently employed, but other tests were also used, including the insulin tolerance test (ITT, the “gold-standard”), the ACTH infusion, and the CRH tests.

Table 6: Diagnostic Tests Not Commonly Used to Diagnose and Differentiate Adrenal Insufficiency

Test / Sampling

Cortisol Response

Prolonged ACTH stimulation test
Depot or iv infusions 250µg cosyntropin over 8hrs(A): cortisol/24hr urinary cortisol/17OHCS before and after infusion or over 24hrs on 2(or3) consecutive days(B)

Physiologic response:A:24hr urinary 17-OHCS
excretion increase 3-5-fold; serum cortisol>20μg/dL (550nmol/L) at 30’ and 60’; >25μg/dL (690 nmol/L) at 6-8hrs post-initiation infusion;B: at 4hrs >1000nmol/L (36μg/dL) beyond this time, no further increase; SAI: delayed response at 24 and 48hrs than 4hrs; PAI no response at either time

THERAPY

Glucocorticoid withdrawal is indicated when the use of the steroid is no longer needed or when significant side effects develop. The suggested method of glucocorticoid withdrawal is dose tapering to avoid the occurrence of AI.

Adrenal insufficiency is a potentially life-threatening medical emergency when presenting as adrenal crisis, which requires prompt treatment with hydrocortisone and fluid replacement. Once, clinically suspected, treatment should be initiated and not be delayed while waiting for definitive proof of diagnosis. Blood samples should be obtained for measurement of cortisol concentrations later, and the management approach should be similar to the resuscitation of any critically ill patient.

There is currently no consensus regarding rapid or slow tapering of glucocorticoids and exacerbation and/or relapse rates of the underlying diseases. The key action is that glucocorticoid withdrawal should not be abrupt. In clinical practice, patients being on any steroid dose for less than 2 weeks are not likely to develop adrenal suppression and are advised to stop therapy without tapering. The possible exception to this is the patient who receives frequent "short" steroid courses, as in asthma treatment. In longer regimens, the objective is to rapidly reduce the therapeutic dose to a physiologic level of cortisol (equivalent to 10-15 mg/ms/d) (Table 7). However, a recent systematic review of 73 studies demonstrated evidence of AI following low doses and short durations of glucocorticoid administration at less than 5 mg prednisolone equivalent dose/day, less than 4 weeks of exposure, cumulative dose less than 0.5 g, and following tapered withdrawal.

Table 7: Tapering After a Long-Term Glucocorticoid Regimen

1. Reduction by 2.5mg prednisolone or equivalent

every 3-4 days over few weeks

2. Slower withdrawal

until physiological level achieved (5-7.5mg of prednisolone)

3a. Decrease by 1mg/d prednisolone or equivalent

every 2-4weeks (depending patient's general condition) until medication cessation

Other tapering regimens suggest switching the patient to an alternate day administration of intermediate action glucocorticoids before cessation of treatment. Irrespectively of the tapering regimen used, if a glucocorticoid withdrawal syndrome, AI or exacerbation of the underlying disease develops, the dose being given at the specific time should be increased or maintained longer. Recent systematic reviews implied that the evidence for the tapering regimens used nowadays is not robust, despite the fact that rapid reduction to a physiologic glucocorticoid dose (5-7.5 mg prednisolone daily or equivalent), and the slow reduction thereafter, is the most frequently used regimen for clinicians.

Care should be given during the tapering regimens period on the interpretation of laboratory tests for cortisol levels measurement. The steroid dose before the test should be omitted (hold off evening and morning dose for hydrocortisone or prednisolone, longer for the other synthetic glucocorticoids); if serum cortisol secretion at 08:00h is > 15μg/dL, the tapering regimen changes to a rapid tapering off of exogenous glucocorticoids. Moreover, there are conditions that affect cortisol-binding globulin concentration (CBG) (↓: inflammation, nephrotic syndrome, liver disease, immediate postoperative period or requiring intensive care, rare genetic disorders; ↑: estrogen, pregnancy, mitotane). Systemic estrogens should be discontinued at least for 4 weeks prior to testing; estrogen patches are preferred since they do not affect CBG. Different criteria may apply according to the cortisol assay.

FOLLOW-UP

Since, there is evidence that AI may persist in 15% of patientsfor more than 3 years after glucocorticoid withdrawal, careful monitoring of patients and gradual glucocorticoid withdrawal should always be performed to avoid manifestations of adrenal suppression and/or an adrenal crisis or reactivation of the underlying disease. In general, plasma ACTH concentrations are not helpful in estimating the optimal glucocorticoid dose whereas mineralocorticoid replacement is not required.

All patients treated with glucocorticoids long-term should receive detailed instructions for glucocortiocoid supplementation equivalent to 100-150mg of hydrocortisone during major stresses (surgery, fractures, severe systemic infections, major burns) until their HPA axis fully recovers and to carry means of identification (medical alert bracelet).

Since full HPA axis recovery may take as long as one year or even longer, abrupt cessation of glucocorticoid treatment or quick tapering can precipitate an acute AI crisis. The diagnosis is a medical emergency, and treatment should be the immediate administration of fluids, electrolytes, glucose, and parenteral glucocorticoids.

CLINICAL RECOGNITION

Patients with prolactinomas come to clinical recognition because of the effects of elevated prolactin levels or tumor mass effects. The most typical symptoms of hyperprolactinemia in premenopausal women are oligo/amenorrhea (approximately 90%) and galactorrhea (approximately 80%). Non-puerperal galactorrhea may occur in 5-10% of normally menstruating, normoprolactinemic women, and therefore is suggestive, but not definitive, of hyperprolactinemia. However, when oligo/amenorrhea is associated with galactorrhea, about 75% of women will be found to have hyperprolactinemia. Galactorrhea is reported in ~10% of cases in men with prolactinomas and is virtually pathognomonic of a prolactinoma. Hyperprolactinemia inhibits the pulsatile secretion of gonadotropin releasing hormone via interfering with hypothalamic kisspeptin-secreting cells via the

PATHOPHYSIOLOGY

Prolactinomas comprise 25 to 40% of all pituitary adenomas. The vast majority of prolactinomas are sporadic. Familial cases of prolactinomas are very rare and occur usually in association with Multiple Endocrine Neoplasia type 1 or the Familial Isolated Pituitary Adenoma syndrome. Genetic testing for young-onset macroprolactinomas should include the MEN1 and AIP genes. Similar to other types of pituitary adenomas, prolactinomas arise from a single transformed cell (lactotroph) with monoclonal proliferation. A number of candidate genetic alterations involved in the genesis and progression of prolactinomas have been looked for but no specific mutations have been found that account for more than a handful of cases at this point.

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS

The majority of patients with hyperprolactinemia do not actually have prolactinomas (Table 1). Drug-induced hyperprolactinemia is the most common, and a number of physiological conditions, including stress (psychological or associated with acute illness), exercise, and sleep can also cause prolactin elevations. The hyperprolactinemia caused by drugs and other non-prolactinoma causes is usually <150 ng/mL (3000 mU/L). Many medications block dopamine release or action, the most common being antipsychotic medications, verapamil and metoclopramide. The best way to determine whether hyperprolactinemia is drug-induced or not is to discontinue the drug or switch to another drug in a similar class that is not known to cause hyperprolactinemia and see if the prolactin levels return to normal within 72 hours. The best example is the partial dopamine receptor agonist aripiprazole, which has been shown to be effective in attenuating antipsychotic medication-induced hyperprolactinemia.

A variety of suprasellar lesions cause hyperprolactinemia because compression of the hypothalamus or pituitary stalk results in decreased dopamine reaching the lactotrophs. These can be mass lesions, such as craniopharyngiomas or meningiomas, or infiltrative disease, such as sarcoidosis and Langerhans cell histiocytosis. The high estrogen levels of pregnancy cause lactotroph hyperplasia and hyperprolactinemia, so pregnancy must always be excluded. The estrogen levels produced by oral contraceptives or post-menopausal hormonal replacement therapy generally do not cause hyperprolactinemia. Hypothyroidism and renal failure (serum creatinine >2 mg/dL (176 µmol/L)) can also cause hyperprolactinemia. Thus, the initial laboratory evaluation involves repeat measurement of prolactin, measurement of TSH and serum creatinine, and a pregnancy test. Unless there is very good evidence for these conditions or drug-induced hyperprolactinemia, even patients with mild hyperprolactinemia should be evaluated with radiological methods, preferably MRI, to distinguish among idiopathic hyperprolactinemia, microprolactinomas, and large mass lesions. Measurement of IGF-1 is recommended for patients presenting with hyperprolactinemia and pituitary adenomas as prolactin may be elevated in up to 50% of patients with GH-secreting tumors.

Special caution is needed when two-site (‘sandwich’) prolactin assays are used, as patients with large prolactinomas and very high prolactin levels may appear to have prolactin levels that are normal or only modestly elevated, thus mimicking a large, non-functioning adenoma. This “hook effect” is due to saturation of the assay antibodies and prolactin levels should always be remeasured at 1:100 dilution in patients with large macroadenomas and normal to modestly elevated prolactin levels.

Sometimes prolactin levels are elevated due to increased amounts of macroprolactin. Macroprolactin consists of high molecular weight prolactin variants that are either aggregates with immunoglobulins or dimers, and have diminished biologic potency. Macroprolactin can be detected in the serum by precipitating the complex with polyethylene glycol. In normal individuals, macroprolactin comprises < 30% of circulating prolactin; therefore, if after precipitation with polyethylene glycol the prolactin levels in the supernatant are > 70% of the upper limit of normal for the assay, the patient can be assumed to have true hyperprolactinemia and not an elevation due simply to macroprolactin.

Macroprolactinemia has usually been found in patients with equivocal symptoms and not those typically due to hyperprolactinemia. A lack of recognition of the presence of macroprolactin can lead to unnecessary laboratory investigations, imaging, and pharmacologic or surgical treatment.

When no pituitary lesions are seen by radiological studies and other known causes have been excluded, the diagnosis of idiopathic hyperprolactinemia is made; in long term follow-up, although prolactin levels may rise to over 50% of the baseline in 10-15% of the patients, only about 10% develop detectable microadenomas, one-third resolve their hyperprolactinemia without specific intervention, and prolactin levels remain stable in most patients.

TREATMENT

Figure 1. Serum prolactin measurement is required in all patients presenting with hypothalamic-pituitary lesions before surgery is accomplished (Figure courtesy of D. Korbonits)

Not all patients require treatment. If a patient with a microadenoma or idiopathic hyperprolactinemia presents with non-bothersome galactorrhea and has normal estrogen/testosterone levels they can simply be followed with periodic prolactin levels. Similar patients who may have amenorrhea but are not interested in fertility may be treated with estrogen replacement. However, for most symptomatic patients, a dopamine agonist is the therapy of choice. Dopamine agonists normalize prolactin levels, correct amenorrhea-galactorrhea, and decrease tumor size by more than 50% in 80-90% of patients, with cabergoline generally being more efficacious and better tolerated than bromocriptine. Thus, defining whether a pituitary tumor is a prolactinoma is crucial for optimal patient management since it is reasonable to use cabergoline as first-line therapy even in patients with visual field defects as long as visual acuity is not threatened by rapid progression or recent tumor hemorrhage (Figure 1). Starting dose in these cases could be higher than usual and some experts suggest 0.5 mg/day with close in-patient monitoring.

Vision often starts to improve within days after the initiation of dopamine agonist therapy. Cabergoline is usually initiated at 0.25-0.5 mg/week (taken initially carefully a with meal just before bedtime, to reduce nausea and improve compliance), whereas the initial dose of bromocriptine is 1.25 mg/day. About 40-50% of patients, whose prolactin levels normalize and tumors shrink to the point of non-visualization, can be tapered off cabergoline without tumor re-expansion. Factors associated with greater risk of recurrence are the presence of pituitary deficits at diagnosis and higher prolactin levels, both at diagnosis and before withdrawal.

A rare but significant side-effect of dopamine agonist treatment is cerebrospinal fluid leakage (CSF) leak, due to the rapid shrinkage of a large prolactinoma allowing CSF to escape if significant damage is present at the fossa floor. Patients should be advised to present if clear fluid appears and this should be tested for beta-2 transferrin. If positive, patients need urgent neurosurgical input with transnasal surgery or lumbar drain being possible approaches in addition to antibiotic therapy, if necessary. Discontinuing dopamine agonist therapy is not usually recommended as it may cause recurrence of the tumor. Dopamine agonist therapy has been implicated as a precipitating factor for pituitary apoplexy in patients with prolactinomas. Nonetheless, prolactinomas are, by themselves, more prone to bleeding, and the reported prevalence of pituitary apoplexy in macroprolactinomas treated with dopamine agonists, ranging from 1% to 6%, is not significantly different from the rate recorded in untreated prolactinomas. Further precipitating factors which have been associated with pituitary apoplexy are cerebral angiography, surgical procedures, head trauma, dynamic tests, anticoagulation therapy, and pregnancy.

A well-described side-effects of dopamine agonists include psychiatric complications, such as depression, anxiety, insomnia, hallucinations, mania. More recently impulse control disorders have also been described in pituitary adenoma patients. The underlying mechanism is related to an interaction between the dopamine agonists and the D3 receptor in the mesolymbic system. Impulse control disorders can manifest as hypersexualism, gambling, compulsive eating, compulsive shopping, and “punding” (compulsive performance of and fascination with repetitive mechanical tasks, for example assembling and disassembling household objects or collecting or sorting various items), with hypersexualism and gambling being the most commonly observed in pituitary patients. Hypersexualism has also been described in teenage children. Although impulse control disorders are infrequent, they have the potential to cause devastating consequences on patients’ life and clinicians should be sensitive to these potential side-effects discussing it with the patient at the start of treatment and during long-term follow-up. Discontinuation of the dopamine agonists usually reverses these side-effects.

In some cases, prolactinomas appear to be resistant to a dopamine agonist, but it is important to ensure compliance and to be certain that the underlying lesion is a prolactinoma and not some other cause of hyperprolactinemia. About 50% of patients resistant to bromocriptine will respond to cabergoline. Most patients resistant to standard doses of cabergoline respond to larger doses. Previous reports in patients taking cabergoline for Parkinson’s disease have shown that doses >3 mg/day may be associated with cardiac valvular abnormalities. Whether similar valvular changes occur in patients receiving low-dose cabergoline for treatment of hyperprolactinemia is still debatable. Common practice has been to perform periodic echocardiograms every 12 to 24 months in patients taking >2 mg/week. However, a clinically significant association between low-dose cabergoline and cardiac valvulopathy is not supported by a large recent multicenter follow-up study. More recently, a meta-analysis of case-control studies evaluating patients who had received ³6 months cabergoline treatment for hyperprolactinemia reported an increased risk of tricuspid regurgitation in the cabergoline-treated patients compared to controls. Nevertheless, these results were mainly influenced by the results from a single center and in the majority of the reviewed studies there were no cases of moderate-severe tricuspid regurgitation in either group. Furthermore, neither cumulative dose nor treatment duration was associated with an increased risk of moderate-severe valve lesions and none of these lesions were found as a result of cardiac symptoms. Therefore, these data would suggest that some degree of monitoring is appropriate, although at substantially reduced frequency than currently recommended. Indeed, some experts suggest echocardiographic monitoring should be reserved for those patients with an audible murmur, those treated for more than 5 years at a dose of more than 3 mg per week, or those who maintain cabergoline treatment after the age of 50 years.

An alternative approach is transsphenoidal surgery, which has initial remission rates of approximately 75% for microprolactinomas and 40% for macroadenomas, and long-term recurrence rates of nearly 20% and 35%, respectively, when performed by expert neurosurgeons. Transsphenoidal surgery is usually reserved for patients with resistance or intolerance to dopamine agonists; macroprolactinomas with chiasmal compression and visual deficits without rapid improvement on medical treatment; or with acute tumor complications, such as symptomatic apoplexy or cerebrospinal fluid leakage. Complications of hypopituitarism, infections and bleeding are minimal, but increase proportionately with tumor size. Craniotomy for large tumors is rarely curative and is fraught with much higher complication rates. Radiation therapy is reserved for those patients with macroadenomas not responding to either medical or surgical treatment. Radiation therapy in all forms is associated with a high rate of hypopituitarism that develops gradually over many years. Temozolomide, an orally-active alkylating chemotherapeutic agent, is reserved for the treatment of aggressive prolactinomas refractory to other treatment modalities.

FOLLOW-UP

The goals of treatment are to normalize prolactin levels or at least bring them to levels at which gonadal/reproductive/sexual function is normalized and to decrease tumor size. As noted, according to different series, nearly 80% of patients treated with dopamine agonists will reach these prolactin goals and achieve significant tumor size reduction. Once prolactin levels have reached normal or near-normal level, they can just be monitored every 3-6 months for the first year and then every 6-12 months thereafter. Macroadenoma tumor size can be monitored by serial MRI scans and once maximal size reduction has been documented, further scans may not be necessary as long as prolactin levels are being monitored. Whether a second MRI scan is necessary in patient with microadenomas is debatable, if prolactin levels are regularly monitored. It is extremely rare for a tumor to increase in size without there being a significant increase in prolactin levels. Visual field testing should be repeated until they normalize or remain stable and then do not need to be repeated.

PREGNANCY

Dopamine agonists have to be given to allow ovulation to occur and then are usually stopped once pregnancy is diagnosed. In this fashion, the developing fetus has been exposed to the drug for about 4-6 weeks. There do not appear to be any risks for fetal malformations or other adverse pregnancy outcomes with either bromocriptine or cabergoline. Data on exposure of the fetus to cabergoline during the first few weeks of pregnancy have now been reported in more than 900 cases and suggest that cabergoline is as safe as bromocriptine in this context. Dopamine agonists are then reinstituted when breast-feeding is completed. Symptomatic growth occurs in about 23% of macroprolactinomas and about 3% of microprolactinomas in the second or third trimester due both to the stimulatory effect of the high estrogen levels of pregnancy and the withdrawal of the dopamine agonist that may have been restraining tumor growth. Visual field testing should be carried out each trimester in patients with macroadenomas but in those with microadenomas only when they develop visual symptoms or progressive headaches. MRI scans (without gadolinium) are done in those patients who develop visual field defects or severe headaches when a therapeutic intervention is contemplated. Prolactin levels may rise during pregnancy when there is not a change in tumor size and conversely, some tumors enlarge without an associated rise in prolactin; therefore, measurement of prolactin during pregnancy need not be carried out. When there is evidence of significant symptoms and tumor growth, the patient should be restarted on a dopamine agonist. Again, there are fewer data with cabergoline than bromocriptine but there is no particular reason to favor one versus the other in this context. Transsphenoidal surgical decompression can be performed if there is an unsatisfactory response to the dopamine agonist. Delivery of the baby and placenta can also be initiated if the pregnancy is sufficiently advanced.

CLINICAL RECOGNITION

Osteoporosis is a prevalent disease characterized by reduced bone mass and architectural deterioration, which leads to structurally weakened bone and increased risk of fragility fractures. A fragility fracture is defined as a fracture occurring with minimal trauma, such as falling from standing height. These fractures rise exponentially with age and most commonly involve the spine, hip, humerus, and wrist. Vertebral compression fractures are the most common osteoporotic fractures with an estimated 700,000 per year in the United States. However, spine fractures are often found incidentally on imaging done for other reasons since they are often asymptomatic. While there are effective treatments to reduce the risk of fractures, only 23% of patients with fragility fractures receive osteoporosis evaluation and treatment.

PATHOPHYSIOLOGY

Bone is a dynamic organ with continuous remodeling to maintain a healthy skeleton--osteoclasts resorb bone and osteoblasts form new bone. Osteoporosis results from a net increase in bone resorption relative to bone formation. The receptor activator of nuclear factor-kappa β (RANK), RANK ligand (RANKL), and osteoprotegerin (OPG) are key regulators of bone resorption. Interaction between RANKL and RANK stimulates osteoclastic differentiation, while OPG, made by osteoblasts, binds with RANKL and inhibits bone resorption. In addition, the Wnt signaling pathway is a network of proteins that is involved in activating the transcription of genes that direct the differentiation and proliferation of osteoblasts. Sclerostin, produced by the osteocytes embedded in bone, is the product of the SOST gene. Sclerostin reduces the Wnt signaling pathway, thereby, suppressing bone formation by osteoblasts. Some of the key factors that are mechanistically involved in bone turnover are therapeutic targets for emerging osteoporosis treatment. See Table 4 for summary of treatments.

Fragility Fractures

Vertebral compression fractures are associated with substantial morbidity including: acute and chronic back pain, height loss, kyphosis, restrictive lung disease, early satiety, reduced quality of life, and increased mortality. A spine fracture is associated with a 5-fold risk of a subsequent spine fracture and a 2-fold risk of hip and other fractures. Hip fractures are serious fractures that can lead to pain, disability, loss of independence, and high mortality. A Danish registry study published in 2018 found that one-year excess mortality was 20-25% after femur or pelvic, 10% following vertebral, and 5-10% following humerus fractures.

There is a high prevalence of low vitamin D levels among hip fracture patients. Since there is a large care gap for patients with fragility fractures, there are critical ongoing efforts to try to implement inter-disciplinary, hospital-based approaches to advance fracture care. It is imperative to ensure timely outpatient follow-up to correct the vitamin D deficiency, evaluate patients for other secondary causes of osteoporosis, and institute osteoporosis treatment. See Treatment section for further description of management of these fractures.

DIAGNOSIS and DIFFERENTIAL

Assessment of osteoporosis risk factors and measurement of bone mineral density (BMD) by dual energy x-ray absorptiometry (DXA) are important to determine which individuals are at increased risk of fractures. Low bone mass (osteopenia) is present when the BMD is between 1.0 and 2.5 SDs below peak bone density of young, healthy individuals. More than 50% of fragility fractures occur in these patients. Osteoporosis, according to the World Health Organization, is defined as a BMD ≤-2.5 SDs of young normal. BMD testing is typically measured at the proximal femur and lumbar spine, though the 1/3 radius should be measured in patients with hyperparathyroidism (https://www.iscd.org/official-positions/). The National Osteoporosis Foundation (NOF) currently recommends that women >65 years, men >70 years, and postmenopausal women and men >50 years with risk factors or low trauma fracture receive screening DXA scans. The NOF recommends monitoring osteoporosis by an annual measurement of a patient’s height, preferably with a mounted stadiometer, and BMD testing 1-2 years after initiating therapy and every 2 years thereafter. Because spine fractures are often not clinically evident, imaging for spine fractures (vertebral fracture assessment by DXA or X-ray) is recommended, particularly in older adults with osteopenia and after a low trauma fracture or glucocorticoid use (See Table 1).

The FRAX® calculator was designed to quantify an individual’s absolute fracture risk (http://www.shef.ac.uk/FRAX). In addition to BMD, the following risk factors are included--ethnicity, age, body mass index, prior fracture history, glucocorticoid use, alcohol use, smoking, rheumatoid arthritis, and other secondary causes of osteoporosis. If the 10-year absolute fracture risk is ≥3% for hip fractures or ≥20% for other major osteoporotic fractures, pharmacologic therapy should be considered. Note that the FRAX calculator is not designed for those with osteoporosis on BMD testing but mainly for those with low bone mass.

Using a specialized software (incorporated in DXA machines), Trabecular Bone Score (TBS) can be generated from lumbar spine DXA images and is a measure that reflects bone microarchitecture and predicts fracture risk independent of bone density. TBS can now also be incorporated in the FRAX score.

Table 1. Imaging Assessment Recommendations

DXA Tests:

- Women aged ≥65 and older men aged ≥70

- Younger postmenopausal women and men aged 50-69 with risk factors for bone loss or fractures

- Adults aged ≥50 who had a fragility fracture

- Adults with a medical condition or taking a medication associated with bone loss and/or fractures

Vertebral Imaging Tests:

- Women aged ≥70 and men aged ≥80 if BMD T-Score is ≤ -1.0

- Women aged 65 to 69 and men aged 70 to 79 if BMD T-Score ≤ -1.5

- Postmenopausal women and men aged ≥50 with specific risk factors:

· Historical height loss of ≥1.5 inches (4 cm)

· Prospective/interval height loss of ≥0.8 inches (2 cm)

· Low trauma fracture in adulthood

· Glucocorticoid therapy

When the diagnosis of a low bone density is made, a work-up to look for secondary causes of osteoporosis should be considered. See Table 2.

TREATMENT

Fractures

The management of a vertebral compression fracture involves both pharmacologic and non-pharmacologic approaches. The acute pain typically subsides over several weeks, but pain management with non-steroidal anti-inflammatory drugs, neuropathic pain agents, or narcotics may be needed. A 2-4 week course of calcitonin, administered as one spray (200 IU) per day intranasally, may help patients who need additional acute pain management. Vertebral fractures are common in older adults and secondary fracture prevention is important. Teriparatide, abaloparatide, denosumab, bisphosphonates, and raloxifene may reduce back pain by preventing new vertebral fractures.

Procedures such as vertebroplasty or kyphoplasty have been thought to be effective for acute fracture pain; however, this finding has not been replicated across studies. This lack of a clear benefit is also offset by the small but serious risks of these procedures, which include epidural cement leak leading to possible nerve root compression, osteomyelitis, cement pulmonary embolism, and the possibility of subsequent vertebral fractures in adjacent vertebrae. The 2016 osteoporosis guidelines from the American Association of Clinical Endocrinologists concluded that the role for these surgical procedures in the treatment of vertebral fractures remain uncertain. A Cochrane review published in 2018 found no demonstrable clinically important benefits for vertebroplasty compared with placebo (sham procedure), and the results did not differ according to duration of pain (≤6 weeks vs. >6 weeks). If vertebral augmentation is considered in select patients with disabling spine fractures, osteoporosis treatment should be initiated concurrently.

Glucocorticoid-induced osteoporosis affects the spine greater than other sites. Glucocorticoids have a major effect on reducing bone formation and also increase bone resorption. Thus, there are two sites for targeted intervention—anabolic and anti-resorptive treatments, respectively. The American College of Rheumatology has recommended starting bone protection therapy for adults ≥40 years taking prednisone at a dose of ≥2.5 mg/day for ≥3 months if at moderate to high risk for fracture (i.e., FRAX 10-year risk of major osteoporotic fracture >10%, FRAX 10-year risk of hip fracture >1%, osteoporosis by bone density criteria, or prior osteoporotic fracture). The Food Drug Administration (FDA) has approved the following anti-resorptive agents — risedronate, alendronate, zoledronic acid, and denosumab — and the anabolic agent teriparatide for glucocorticoid-induced osteoporosis. In a randomized trial, teriparatide was superior to alendronate in preventing BMD declines at the spine and hip.

With regards to hip fractures and the use of zoledronic acid once yearly, the timing of this FDA-approved treatment for secondary fracture prevention is important. There is a significant reduction in vertebral and non-vertebral fractures and mortality as well as an increase in hip BMD in those who receive zoledronic acid and supplemental vitamin D between two weeks and 90 days following a hip fracture

.

Osteoporosis

Adequate calcium and vitamin D intake are essential. In 2010, the Institute of Medicine (IOM) set new recommendations for daily calcium and vitamin D requirements. See Table 3.

Obtaining calcium through the diet is preferred. However, if taking calcium supplements for those on proton pump inhibitors, calcium citrate (e.g., Citracal®) is preferred given better absorption over calcium carbonate and can be taken on an empty stomach. Preparations of Citracal® include Maximum Plus (315 mg of calcium per tablet) and Petite (200 mg of calcium per tablet). Calcium carbonate (e.g., Oscal®, Caltrate®), ranging from 500 to 600 mg per tablet, should be taken with food to allow optimal absorption.

Vitamin D deficiency is a prevalent problem. The IOM guidelines recommend a daily dose of vitamin D3 of 600 IU for individuals ≤70 years of age and 800 IU daily for those ≥71. Other societies recommend 800-1000 IU of vitamin D for high-risk adults with osteoporosis. Patients with vitamin D deficiency need much higher doses. Although there is debate, the NOF and other organizations currently recommend a 25-OH D level ≥30 ng/mL. There are ongoing, population-based studies that are evaluating the effects of supplemental vitamin D on fractures and bone health measures.

Mild flu like syndrome during and after ZA infusion (pre-treat with acetaminophen); ZA should not be given if severe renal impairment (GFR <35 mL/min). After a hip fracture, vitamin D and ZA should be initiated 2 weeks to 90 days after the fracture.

CURRENT THERAPEUTIC APPROACH

Pharmacologic treatment is indicated for those with osteoporosis by BMD criteria; fragility vertebral or hip fracture regardless of BMD; fragility fracture of the pelvis, proximal humerus, or wrist with osteopenic range BMD; and elevated FRAX scores.

The most commonly used therapy is a bisphosphonate, which has long skeletal retention, decreases bone turnover, and reduces the risk of fractures (see Table 4). Alendronate, risedronate, and zoledronic acid decrease vertebral, non-vertebral, and hip fractures, whereas ibandronate decreases vertebral but not hip or non-vertebral fractures. There is concern about the association of its long-term use and risk of atypical femur fractures. These fractures (1) can occur along the subtrochanteric femur, (2) are associated with minimal or no trauma, (3) are in transverse or short oblique configuration, and (4) usually are complete fractures through both cortices. Some patients have prodromal symptoms of thigh or groin pain in the affected leg; bilateral atypical femur fractures may also be present. The incidence of these types of fractures is very low, and the consensus has been that the number of fractures prevented far exceeds the number of these fractures occurring as a result of bisphosphonates. According to the available limited, post-hoc data analyses, continuation of therapy after 3 years for zoledronic acid and 5 years for oral bisphosphonates may be considered in those with hip, spine, or multiple other osteoporotic fractures before or during therapy, osteoporosis at the hip after treatment, or high fracture risk. According to the 2011 FDA review, more data are needed concerning long-term bisphosphonate use. Until these data are available, annual evaluation and follow-up should involve decisions as to whether a 1-2 year or greater bisphosphonate holiday is needed, according to each individual’s risk, or to consider the use of alternative treatments as needed. It is important, however, to follow patients with a history of low bone mass or osteoporosis who are on a bisphosphonate holiday. Another rare complication is osteonecrosis of the jaw, which usually occurs in the setting of an invasive dental procedure. This complication is primarily seen in cancer patients who are receiving zoledronic acid on a monthly basis to prevent cancer-related fractures.

Denosumab, FDA approved in June 2010, is a monoclonal antibody that reduces RANKL, inhibiting the cellular mechanisms underlying bone resorption. It decreases the risk of vertebral, non-vertebral, and hip fractures and can be judiciously used in those with renal dysfunction. Denosumab has also been associated with rare cases of atypical femur fractures and osteonecrosis of the jaw. Of note, a drug holiday from denosumab is not recommended due to rebound bone loss and risk of multiple vertebral fractures with discontinuation. If denosumab is to be discontinued, it should be followed by bisphosphonate treatment.

Anabolic agents teriparatide (1-34 recombinant PTH) and abaloparatide (1-34 recombinant PTHrP) stimulate overall bone formation, improve bone structure, increase BMD particularly at the spine, and reduce risk of vertebral and non-vertebral fractures. In postmenopausal women with history of vertebral fracture, teriparatide has been shown to reduce incident vertebral and clinical fractures more than risedronate. Abaloparatide appears to be more effective at increasing bone density at the total hip compared to teriparatide and is less likely to cause hypercalcemia. They are administered as daily subcutaneous injections, and duration of therapy is limited to 2 years. In rodents, there was an increase in the risk of osteosarcoma. Thus, this treatment should not be used in patients with active malignancy, history of radiation therapy, elevated alkaline phosphatase, or Paget’s disease. Anabolic agents should be followed by anti-resorptive therapy to consolidate gains in BMD.

OTHER EMERGING THERAPIES

Other new therapies under investigation include sclerostin inhibitors. Sclerostin, produced by osteocytes, decrease osteoblast differentiation and bone formation. Clinical studies of romosozumab have shown reduced risk of vertebral and nonvertebral, and hip fractures compared to placebo as well as alendronate. However, there were more adjudicated serious cardiovascular events in the romosozumab treatment arm compared to the alendronate arm. Thus, the FDA is currently evaluating this agent.

FOLLOW-UP

Once an initial bone density is measured, a follow-up BMD should be done 1-2 years after the initial screening and depending on whether pharmacologic therapy was initiated. Biochemical bone turnover markers and collagen breakdown products (e.g., N-telopeptide, C-telopeptide, collected in the morning) at baseline and after 3 months of treatment may be helpful in select patients to determine patient response to a therapeutic intervention. Clinical musculoskeletal evaluation and annual height measurements are important in the identification of spine fractures. Fragility fractures increase exponentially with advancing age, and evaluation and treatment of new fractures are critical for secondary prevention of fractures and healthy aging.

CLINICAL RECOGNITION

The acute passage of a kidney stone is the 9th most common cause of emergency room visits. Approximately 7-8% of women and 11-16% of men will have stone disease by age 70. The acute syndrome complex called renal colic implies obstruction of the collecting system or ureter, and the most common cause of obstruction is a kidney stone. Kidney stone colic is relatively constant in contrast to intestinal or biliary colic, which waxes and wanes or comes in waves. The onset of pain heralds the entrance of a stone into the collecting system and the ensuing obstruction. The intensity and location of the pain may vary with stone size, stone location, degree of luminal obstruction, and the suddenness of the obstruction but flank pain is very common. Referred genital pain is common with distal ureteral stones. Symptoms typically begin at night or the early morning hours with abrupt onset and awakening the patient from sleep. During the day, the onset of symptoms may follow heavy exercise and may be more gradual with an occasional prodrome of unilateral discomfort in the flank, testis or vulva on the side of the obstruction. The pain then becomes continuous, steady; and progressively more severe as it approaches a peak. For some, there are acute paroxysms of increasingly intense pain. Anorexia, nausea and vomiting commonly appear with the pain, and gross hematuria may be present. Overall, one-third of patients have a relatively rapid onset and reach peak pain in 30 minutes or less. Untreated, the pain may last for 4 to 12 hours, but most patients have presented to the emergency room by the time the pain becomes continuous, usually by two hours into the colic. Upon presentation, the pain is described as a 9 or 10 out of a scale of 1 to 10. Chills and fever may be present as well and should raise concern for infection as these symptoms are usually not present in uncomplicated urolithiasis. Similarly, hypotension also raises the likelihood of infection as the pain associated with renal colic typically induces hypertension and tachycardia.

PATHOPHYSIOLOGY

Stone-induced renal colic refers to an intraluminal cause, but non-stone related external compression of the ureter can induce the same symptom complex and be confused with the intraluminal presence of a stone. Renal colic can arise from three mechanisms: urinary obstruction, the most common cause, is due to a direct increase in intraluminal pressure and stretch of the nerve endings in the mucosa; local ureteral mucosal or collecting system irritation from direct contact of the stone; and interstitial edema and stretch of the renal capsule, particularly when there is a concomitant pyelonephritis. Stones are more likely to hang up and obstruct at naturally narrow regions of the upper urinary tract including the ureteropelvic junction, crossing of the iliac artery and vein, pelvic brim, and the ureterovesical junction.

DIAGNOSIS and DIFFERENTIAL

Diagnosis

The diagnosis is strongly suspected by the symptom complex. The examination reveals costovertebral angle tenderness with dysesthesia of the skin overlying the area along the flank, lower abdomen, groin, or genitalia. Gross or microscopic hematuria is present in 60% to 90% of patients with renal colic but is not required for the diagnosis.

Children with renal stones may present with more vague abdominal symptoms compared to the symptom complex in adults. Therefore, abdominal pain in children and adolescents should call for a urologic evaluation if no diagnosis has been reached.

Acute onset of continuous, aching or dull pain that is non-colicky or flank pain without radiation to or toward the groin suggests a non-stone etiology. Common causes of acute non-colicky pain are listed in Table 2.

Table 2. Differential Diagnosis of Acute Non-colicky Renal Pain

Renal vein thrombosis

Pyelonephritis

Renal cortical abscess

Poststreptococcal glomerulonephritis

Rapidly progressive glomerulonephritis

Polycystic kidney disease

Medullary sponge kidney

DIAGNOSTIC TESTING

Imaging

The definitive diagnosis of acute renal colic relies upon radiographic imaging of the kidney and urinary tract to demonstrate the location, number, and size of the stones as well as the degree of obstruction. Non-contrast CT (NCCT) has become the imaging study of choice when evaluating patients with acute flank pain and suspected ureterolithiasis. It has both a high sensitivity and specificity for demonstrating the presence of stones and the ability to detect other abnormalities that maybe accounting for the symptoms. In addition, it has the advantage of providing information regarding stone number, location, size, and in some instances stone composition. It can also reveal signs of obstruction. The majority of patients evaluated by NCCT require no further imaging to determine the need for urological intervention. Many now advocate the use of low dose NCCT for the diagnosis of renal stones to reduce radiation exposure, particularly if the BMI is less than 30kg/m2.

Ultrasound is also a sensitive method for detecting ureteral stones in patients with renal colic and can be used as the initial imaging method in investigating these patients. However, the quality of ultrasound information is operator dependent and ultrasound has decreased diagnostic sensitivity. Kidney stones are common during pregnancy. Because fetal radiation exposure should be avoided, ultrasound is the primary radiologic procedure followed by MRI if necessary in pregnant women. NCCT should be used only in rare instances in pregnancy. In children ultrasound is the initial imaging procedure followed by low dose NCCT if needed.

A radiographic study done while the patient is in the emergency room will establish a definitive diagnosis, especially if it can exclude other causes of acute abdominal pain; will avoid a prolongation of the painful episode; avoid delay in treatment; and reduce the risk of loss of renal function when complete obstruction is present.

Laboratory Studies

The laboratory studies that should be obtained are shown in Table 3.

Table 3. Laboratory Studies

Complete Blood Count (CBC)

Increased neutrophils may be due to a stress response or infection

Electrolytes

Creatinine

Usually not markedly increased. A marked increase suggests solitary kidney, baseline kidney disease, or pre-renal injury due to dehydration

Calcium

Hypercalcemia suggests the mechanism of stone formation and requires further evaluation

Urine culture and sensitivity if U/A abnormal or other signs of infection

Patients should be instructed to filter their urine in the hopes of retrieving a stone for analysis. Knowing the stone composition will help guide future preventive therapy.

TREATMENT

The goals of management during the acute phase of stone obstruction and renal colic includes: pain control and diagnostic procedures to determine the presence of a kidney stone in the collecting system and the extent of obstruction.

Pain management should be started soon after the patient arrives in the emergency room and should be continued until the episode has resolved. Nonsteroidal anti-inflammatory drugs (NSAIDS) (for example diclofenac, indomethacin or ibuprofen) are effective first line agents for acute pain treatment. If the pain persists or NSAIDS are contraindicated, narcotics, such as morphine sulfate 0.1 mg per kg body weight IM every four hours or meperidine (Demerol) 1.0 mg per kg body weight IM every three to four hours, may be used. Intravenous lidocaine (1.5mg/kg) is another option that has been shown to be effective in reducing renal colic. Anti-emetic agents may be given along with the narcotics as nausea and emesis may occur with stone passage and commonly complicate narcotic use. If medical treatment is not sufficient consultation with urology and consideration of drainage or stone removal is indicated.

Alpha blockers, such as tamsulosin, may be used to facilitate the clearance of kidney stones. In a Cochrane review of 67 studies with 10,509 participants it was concluded that “alpha-blockers likely increase stone clearance but probably also slightly increase the risk of major adverse events (hypotension, syncope, palpitations, tachycardia). Subgroup analyses suggest that alpha-blockers may be less effective for smaller (5 mm or smaller) than for larger stones (greater than 5 mm)”. Smaller stones are more likely to spontaneously pass and therefore the advantages of alpha blockers are minimized but they may induce more rapid clearance. Additionally, alpha blockers also reduce renal colic.

The size of the stone is a major determinant of the need for surgical management vs. conservative management. Stones vary from less than 2 mm to greater than 2 cm in diameter. The majority of stones are less than 4 mm in width, small enough to pass spontaneously in most patients. A stone’s size is an important factor together with symptom severity, degree of obstruction, presence or absence of infection, and level of renal function in deciding whether to manage the stone initially by observation, awaiting spontaneous passage, or to intervene with a surgical procedure. Stones with a width of 5 mm or less have a 50% chance of spontaneous passage if in the proximal ureter and a better chance if in the distal ureter. Overall, for stones ≤5 mm, approximately 68% will pass spontaneously. For stones >5 mm and ≤10 mm, an estimated 47% will pass spontaneously. One study found that stones > 9mm had only a 25% chance of spontaneous passage. Distal stones are more likely to clear than proximal stones (proximal ureter 48%, mid-ureter 60%, distal ureter 75% passage rate). Thus, in many patients with renal colic symptomatic treatment and close follow-up with the anticipation of stone passage is reasonable. The presence of infection, obstruction, refractory or difficult to treat pain, or deterioration of renal function indicates the need to urological consultation and the consideration of surgical intervention.

Urologic consultation should be obtained for possible surgical intervention for a number of reasons including stones with a low likelihood of spontaneous passage (large stones, proximal location), infection, obstruction, renal insufficiency or worsening renal function, and comorbidities that increase the risk of adverse outcomes (for example pregnancy). Depending upon the circumstances a number of procedures are available including ureteroscopic stone lithotripsy and extracorporeal shock wave lithotripsy for stone removal and percutaneous nephrostomy tube and JJ-stent for urinary drainage.

The presence of urinary tract infection increases the risk for development of pyelonephritis and/or pyonephrosis. Urgent intervention is therefore indicated, again regardless of stone size. Near-total or total ureteral obstruction predicts deterioration of renal function that may start within two weeks of presenting with stone disease and therefore indicates the need intervention.

FOLLOW-UP

Follow-up evaluation should be within one to two weeks of the acute event depending on the extent of intervention and whether there is risk for new obstruction from residual stones. Metabolic evaluation using blood and urine tests may be performed after six weeks of recovery to guide specific preventative therapy. Stone analysis, and the results of urine and blood tests can guide decisions on preventive therapy. It should be recognized that after a first stone episode 30-50% of individuals have a recurrent stone within 10 years.

ABSTRACT

Von Hippel-Lindau (VHL) disease is an autosomal dominantly inherited tumor syndrome. The incidence of VHL disease is about one in 36,000 livebirths and the penetrance is higher than 90%. Similar to other tumor suppressor gene disorders, VHL disease is characterized by frequent development of specific types of tumors in selective organs.

The disease is named after the German ophthalmologist Eugen von Hippel, who identified and described characteristic retinal manifestations, and the Swedish pathologist Arvid Lindau, who discovered the frequent co-occurrence of retinal and cerebellar hemangioblastoma with tumors and cysts in visceral organs. He described the clinical spectrum of VHL disease in detail in a large series of cases from Sweden but also from other European countries. A clinical classification system divides individuals who are affected by VHL disease into two groups: Those predominantly without pheochromocytoma are classified as VHL type 1, and those predominantly with pheochromocytoma are classified as VHL type 2. VHL type 2 is further subdivided into type 2A (with renal cancer) and type 2B (without renal cancer). In type 2C affected patients develop solely pheochromocytomas. Tumorigenesis in patients with VHL disease shares fundamental principles in the different affected organ systems: germline VHL inactivation leads to persistence of microscopic developmentally arrested structures. These microscopic cell clusters already reveal biallelic VHL inactivation and consequent up-regulation of hypoxia inducible factor (HIF) and down-stream targets like VEGF, EPO. Current research for pharmacotherapy of VHL disease targets proteins of the HIF cascade and compounds that lead to upregulation and re-functionalization of mutated VHL protein. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

INTRODUCTION

Von Hippel-Lindau (VHL) disease is an autosomal dominantly inherited tumor syndrome. The incidence of VHL disease is about one in 36,000 livebirths [1, 2]and the penetrance is higher than 90 % [3]. Similar to other tumor suppressor gene disorders, VHL disease is characterized by frequent development of specific types of tumors in selective organs.

The disease is named after the German ophthalmologist Eugen von Hippel, who identified and described characteristic retinal manifestations [4], and the Swedish pathologist Arvid Lindau, who discovered the frequent co-occurrence of retinal and cerebellar hemangioblastoma with tumors and cysts in visceral organs. He described the clinical spectrum of VHL disease in detail in a large series of cases from Sweden but also from other European countries [5, 6].

A clinical classification system divides individuals who are affected by VHL disease into two groups [7]: Those predominantly without pheochromocytoma are classified as VHL type 1, and those predominantly with pheochromocytoma are classified as VHL type 2. VHL type 2 is further subdivided into type 2A (with renal cancer) and type 2B (without renal cancer). In type 2C affected patients develop solely pheochromocytomas[8].

CNS HEMANGIOBLASTOMAS IN VHL SYNDROME

Hemangioblastomas are the index tumors of VHL disease and are frequently the earliest manifestation of the disease. Multiple hemangioblastomas occur frequently in patients with VHL disease. In one major study 127 of 160 patients with VHL-associated hemangioblastomas had multiple tumors [13]. The central nervous system hemangioblastoma burden in VHL disease is associated with partial germline deletions and male sex [14]. The benign slow growing highly vascularized tumors cause neurologic symptoms depending on their size and location [13, 14]. A spinal hemangioblastoma may lead to focal neurologic deficits such as weakness and paresthesias. Posterior fossa tumors may present with ataxia, dysmetria, nystagmus, and slurred speech. Symptoms may also evolve due to CSF obstruction causing signs of increased intracranial pressure or brain stem herniation [3, 11, 15]. Symptoms are usually not caused by the tumor itself but rather by an associated pseudocyst or syrinx, which is caused by vascular leakage from the tumor [16]and which is usually larger than the tumor itself [13]. Polyglobulia has been reported in patients with hemangioblastomas [17]. It occurs in 10% of patients [18]and may cause thrombosis. Removal of the largest hemangioblastoma usually resolves polyglobulia [18].

Diagnosis is established by contrast enhanced MRI of the head and spine [19, 20], which typically identifies a solid enhancing nodule associated with a pseudocyst or syrinx (figure 1).

Patients with VHL disease frequently develop several CNS hemangioblastomas but not all of the tumors need to be removed. Surgery is needed for all symptomatic tumors and for all tumors causing CSF obstruction [13, 21, 22]. Once symptoms occur, they can usually not be reversed by surgery; therefore, surgery may be recommended in a subset of asymptomatic tumors with radiographic progression [22]. Complete surgical removal of the solid tumor is the treatment of choice. If surgery is not possible, radiation therapy may be an alternative. [23-27]. There is currently no established chemotherapy for hemangioblastomas. Substances studied include different tyrosine kinase inhibitors such as semaxanib [28-32], Vatalanib (ongoing trial), Sunitinib [33-36]and Dovitinib [37]as well as pazopanib [38-40]

Surgical resection of hemangioblastomas requires careful dissection in the plane between tumor and CNS tissue. If the tumor is entered, major bleeding will occur. Hemangioblastoma patients harbor a risk for spontaneous or perioperative hemorrhage [41]and preoperative embolization has been recommended for large solid tumors [42, 43]. The tumors can usually be completely removed and permanent new neurologic deficit due to surgery is rare in experienced hands. Intraoperative ultrasound allows for identification of small tumors and control of complete resection of the tumors [44].

Recently intraoperative ICG angiography has been used by different groups. Some of them find it helpful in understanding the vascular anatomy of the lesions, whereas others find it of limited value [45-50]

Hemangioblastomas are composed of a dense capillary network with “stromal” cells in between. Microdissection and genetic deletion analysis revealed the “stromal” cells to represent the neoplastic component of these tumors [51], while the capillary network predominantly represents reactive VEGF-driven angiogenesis. The histogenesis of the neoplastic “stromal” cells has been controversial. Tumor cells stain consistently positive for neuron specific enolase [52-54], neural cell adhesion molecule [55, 56]and vimentin [54-58]. The “stromal” cells appears to represent developmentally arrested VHL-deficient hemangioblast progenitor cells with hematopoietic differentiation potential [59-63], based on the observation of expression of pre-hemangioblastic markers like scl and brachyury [63-66]and the ability of primitive blood island formation and differentiation into early red blood cells [65, 67-69]. Furthermore, anatomic studies on spinal cord and cerebellum of VHL patients revealed numerous developmentally arrested structural elements [70]that serve as potential precursor material for hemangioblastic tumors [71]. In addition to hematopoietic differentiation capacity the tumor cells are also capable of primitive vasculogenesis[72, 73]. It has remained unresolved, however, whether the tumor cells are of mesodermal or neuroectodermal origin.

RETINAL HEMANGIOBLASTOMAS IN VHL SYNDROME

Retinal hemangioblastomas are benign tumors that can occur as a sporadic entity as well as in patients with VHL disease. Tumors frequently occur in multiplicity and bilaterally (in about 50 %). Histologically, retinal hemangioblastomas are identical to CNS hemangioblastomas [74]. High expression of VEGF in these tumors causes vascularization, vascular leakage and exudation, and eventually retinal detachment in the eye.

Annual fundoscopic screening and early treatment of asymptomatic lesions is recommended for VHL patients starting at one year of age. Most peripheral retinal hemangioblastomas are well controlled by laser photocoagulation or cryotherapy [75, 76]. Vitrectomy may be performed in larger tumors [77]. Tumors in the optic disc should be monitored without treatment. Alternative treatments are in experimental stages and include VEGF inhibition [30, 78, 79]and radiation therapy [80]. Recently propranolol has been suggested for treatment of retinal hemangioblastomas [81].

With screening and early treatment of detected lesions, visual prognosis for VHL patients is good: In one major study approximately 8% of the eyes of VHL patients had poor visual acuity of 20/200 or worse with approx. 8% of these eyes requiring enucleation [82]. Genotyping of young patients presenting with paraganglioma or pheochromocytoma can lead to early detection of retinal hemangioblastomas and other VHL manifestations in family members [83].

RENAL MANIFESTATIONS IN VHL SYNDROME

Patients with VHL disease can develop renal cysts and renalcell carcinomas [84-89]. Renal cell carcinomas are malignant tumors. The pathogenetic relationship between renal cysts and renal cell carcinoma has remained unclear. One study suggests rare transition from a cyst to a solid lesion [90]. Histologically, renal cell carcinomas in VHL disease are always of clear-cell type (figure 3), and small carcinomas tend to be low grade [91]. While small renal tumors in VHL disease tend to be low grade and minimallyinvasive [91], their rate of growth varies widely [92, 93].

Renal manifestations are usually multiple and bilateral in patients with VHL disease. They remain asymptomatic for a long time. Advanced cases of renal cell carcinoma may present with hematuria, flank pain, or a flank mass.

Renal cysts in VHL disease usually do not require treatment. Therapy of renal cell carcinoma is targeted towards prevention of metastasis and preservation of kidney function. In contrast to sporadic renal cell carcinoma, nephrectomy is not recommended as primary therapy for VHL-disease-associated renal cell carcinomas. Most specialized centers recommend nephron-sparing surgery for carcinomas that exceed 3 cm in size [85, 94]. Recent work supports the hypothesis, that a diameter of 4 cm is also acceptable [95]. Although the gold standard for treating renal tumors are open and laparoscopic partial nephrectomy, alternative therapies including cryotherapy and radiofrequency ablation are presently utilized [96]. Possible substances for treatment of metastasized disease include pazopanib [97].

PHEOCHROMOCYTOMAS IN VHL SYNDROME

Pheochromocytomas usually are sporadic but in more than 33% of patients can occur in a familial syndrome such as the VHL syndrome [98, 99]. Presence of pheochromocytomas defines VHL disease type 2 (A,B,C) (Figure 4, modified from [100]).

Figure 4. VHL-associated pheochromocytoma

In a series of 246 patients with VHL syndrome, 64 patients (26%) were found to have a pheochromocytoma [101]. In one third, these tumors were “nonfunctional” and did not cause symptoms of catecholamine excess such as hypertension. Utilizing 18F-DOPA functional imaging in 52 patients with von Hippel-Lindau disease, 4 of 10 patients with positive adrenal uptake had elevated catecholamine levels, i.e. 6 of 10 pheochromocytomas were “silent” [102]. Asymptomatic patients with pheochromocytoma have also been reported in 15 of 150 patients seen at the Mayo Clinic [103]and in 19 of 33 patients with adrenal pheochromocytomas that were incidentally discovered [104]. The mean age at diagnosis of VHL patients reported by Walther et al. 1999 [101]was 29 years with a range from age 6 to age 54 years. Bilateral pheochromocytomas in this group were found in 39% of patients. Extra-adrenal pheochromocytomas or paragangliomas in patients with VHL disease can be sympathetic or parasympathetic and, if located in the head and neck, are mostly unable to produce and secrete catecholamines [99, 105-108]. Genotyping of young patients presenting with a functional paraganglioma can lead to detection of other family members with VHL disease [83]. Recent studies in Chinese and Asian Indian patients revealed novel genotype-phenotype correlations in VHL disease [109-111]. Loss of the ability of VHL protein to degrade HIF under hypoxic conditions can promote the development of bilateral pheochromocytomas [112].

In general, extra-adrenal pheochromocytomas have a higher frequency and potential of malignancy than pheochromocytomas located in the adrenal gland [113]. Malignant pheochromocytomas (defined as the presence of chromaffin tissue at locations where such tissue should not be present, i.e. lungs, liver, bone, lymph nodes) are uncommon in patients with VHL syndrome [92, 99, 100, 114, 115]. However, even in children as young as 12 years of age metastatic pheochromocytomas in VHL disease have been observed [116]. Unfortunately, there are no markers yet that can reliably distinguish a benign from a malignant pheochromocytoma [117].

The detection of a pheochromocytoma in patients with VHL syndrome is particularly important, given the possible need for surgical interventions for other tumors such as CNS hemangioblastomas. Just like in any patient with an undetected pheochromocytoma, surgery and other factors can lead to life-threatening hypertensive attacks intraoperatively. During pregnancy, surgery usually should take place in the second trimester and may include interval adrenalectomy [118]. Screening for pheochromocytoma in at high risk patients (VHL type 2A,B,C) should include measurements of urinary catecholamines and fractionated metanephrines, as well as of plasma free metanephrines, acknowledging that normetanephrine is the predominant biochemical marker for adrenal and extra-adrenal VHL-associated pheochromocytomas, and that methoxytyramine a helpful marker for head and neck paragangliomas [119, 120]. Determining the screening age for pheochromocytoma should likely be made dependent on potential beneficial and negative sequelae that could occur if screening were not performed, i.e. malignancy (lower than 5% in VHL disease!), hypertension, radiation exposure from frequent imaging. There is marked intrafamilial variation, and the penetrance of pheochromocytoma may be as late as age 54 years [101, 121]. In a recent study of 37 Danish patients from the national VHL research database and additional international children and adolescents with VHL disease the age range of clinical manifestations (mostly retinal and CNS hemangioblastomas) was from 6 to 17 years of age [122].

At present, experts recommend pheochromocytoma screening be started already in childhood at the age of 8 years [99, 123][9]. The adrenal glands (suprarenal) can be visualized while undergoing an MRI to look for renal abnormalities in patients with VHL disease. More than 70% of pheochromocytomas presenting in children are due to VHL disease. The diagnosis can further be established by abdominal computed tomography and/or magnetic resonance imaging [9].

Given the low frequency rate of extra-adrenal pheochromocytomas (approx. 15%) and malignant pheochromocytomas (< 5%) in patients with VHL disease, only selected patients should undergo 123I-MIBG scanning to search for extra-adrenal or metastatic lesions, before operation [113, 124]. Importantly, (isolated) pheochromocytoma can be the presenting manifestation of VHL syndrome[3, 125]. Approximately 50% of patients with apparently isolated familial pheochromocytoma have VHL disease and approx. 10% of patients with apparently sporadic pheochromocytoma [99, 126, 127], acknowledging that a family history is not always present or reliably obtainable [128]and that even if VHL germline mutations were detected by certified laboratory testing in patients with non-syndromic pheochromocytoma (i.e. in 3 of 182 patients, [129], misdiagnoses can occur.

Treatment of nonmetastatic adrenal pheochromocytoma consists of adrenal sparing (partial) tumor removal, either uni- or bilateral, depending on whether one or both adrenal glands are affected [130-132]. Endoscopic adrenal sparing removal of the pheochromocytoma should be performed in most if not all patients. [133]. Cortical sparing adrenal surgery exhibits < 5% recurrence rates after 10 years of follow-up while preserving normal glucocorticoid function in more than 50% of patients [134]. The perioperative outcome of patients with VHL disease is very good, although they may have a very high noradrenergic secretion compared to patients with neurofibromatosis type 1 and multiple endocrine neoplasia type 2A [135]. Occasional VHL patients with pheochromocytomas exhibit a decline in tumor size after 19 months of sunitinib therapy [136].

Whether nonfunctional pheochromocytomas (clinically only remarkable as adrenal masses on imaging with normal fractionated urinary metanephrines and/or normal plasma free metanephrines) require treatment/surgery remains unclear. Important aspects in this context are the questions how fast such tumors grow, if and when they cause symptoms, and if and when (at what size) they metastasize [137, 138].

EPIDIDYMAL CYSTADENOMAS IN VHL SYNDROME

These non-malignant tumors occur in about half of all male VHL patients [139]. Epididymal cystadenomas consist of cystic and adenomatous areas and arise typically in the caput epididymidis (figure 5). The tumors have been suggested to arise from microscopic precursor structures, which are abundantly observed in the efferent ductiles of the caput epididymidis of VHL patients [140, 141]. Epididymal cystadenomas rarely cause symptoms and have no potential for malignant transformation. In rare cases bilateral obstruction of efferent ductiles and spermatic cords may occur resulting in sterility. Epididymal cystadenomas are well visible on ultrasound.

Women who are affected by VHL disease develop cystadenomas of the broad ligaments, which play no major clinical role.

Most pancreatic tumors in VHL disease are asymptomatic. Extremely rare – and depending on size and location – are bile duct obstruction and/or pancreatic insufficiency. Most patients do not need any treatment. This is important for patients with pancreatic cysts and/or microcystic adenomas. In a recent study of 48 patients with VHL disease, branch duct intraductal papillary mucinous neoplasms were present in 10% [146].

(68)Ga-DOTATOC PET/CT appears to be a very sensitive screening tool in detecting pancreatic neuroendocrine tumors in VHL disease [147]. All patients should be investigated by MRI with intravenous contrast administration. It is very important that imaging is performed in the early arterial phase. In contrast to the multicystic appearance of microcystic adenoma, neuroendocrine pancreatic tumors present as solid lesions and need to be considered for surgical removal. Mutations in exon 3, especially of codons 161/167 are at enhanced risk for metastatic PanNETs [148]. However, most VHL associated pancreatic neuroendocrine tumors are small and slowly growing. In general, VHL associated pancreatic neuroendocrine tumors have a favorable prognosis compared to sporadic tumors [149]. Tumors with a diameter over 2.8 cm should be treated surgically to avoid metastasis according to a recent multicenter study [148]. Resection of pancreatic tumors may also be performed if the patient is undergoing laparotomy for other lesions [150, 151]. In cases of biliary obstruction and/or pancreatic insufficiency treatment consists of placing biliary stents and/or replacing pancreatic enzymes. A new option is organ-sparing endoscopic resection which can be applied to tumors in the tail and the body of the pancreas [152]. Chemotherapy is currently under investigation. Occasional patients respond well to somatostatin analog therapy [153].

ENDOLYMPHATIC SAC TUMORS IN VHL SYNDROME

Endolymphatic sac tumors are benign cystadenomas that arise in the vestibular aqueduct and may extend into the extraosseous portion of the endolymphatic sac, into the petrous bone, and into the inner ear [154, 155]. Large tumors have been reported to extend into the brain [50]. The vestibular aqueduct connects the inner ear with the extraosseous portion of the endolymphatic sac, a dural fold at the posterior surface of the petrous bone. Despite their benign nature these lesions grow locally invasive into the temporal bone due to their origin in the osseous portion of the vestibular aqueduct.

Diagnosis is established by MRI, which shows homogeneous or variable patterns of patchy enhancement and CT (bone window) revealing widening of the osseous portion of the vestibular aqueduct (figure 6).

Radical resection allows for complete excision of the tumors. The preoperative level of hearing can usually be preserved. The timing of surgery depends on the severity of symptoms, the slow but variable growth of the tumors, the possibility of injury to the 7thand 8thcranial nerves and possible bilateral occurrence. Hearing preserving early surgical resection is recommended to enhance the opportunity for complete resection and decrease irreversible audiovestibular symptoms [47]. Endolymphatic hydrops can be detected early on contrast-enhanced delayed FLAIR MRI even before the tumoral mass itself is visible [45]. The role of radiation in the treatment of these tumors remains controversial (see [50]for a review).

PROGNOSIS IN VHL SYNDROME

Before the introduction of clinical screening programs and timely prophylactic treatment of VHL associated lesions, the life expectancy of affected patients used to be impaired with a median survival around 50 years [2, 11]. Nowadays, life expectancy may be significantly improved by clinical screening programs with early detection and treatment of VHL manifestations [158]. Modern management of VHL has meanwhile achieved a life expectancy of additional 10 years [159].

VHL SCREENING

All patients with hemangioblastoma, the index tumor of VHL disease, should receive a careful family history, screening for detection of other lesions associated with VHL (table 2), and should undergo genetic testing for VHL disease [160, 161].

Once the diagnosis of VHL disease is established, patients should undergo an annual screening program in order to identify manifestations early before deficits or metastasis occur. Screening includes periodic contrast enhanced MRI scans. CNS gadolinium accumulation will eventually occur in virtually all VHL patients, however, no pathological effect of this accumulation is known so far [47]. The screening programs vary slightly between different centers. An example of a routine surveillance protocol for von Hippel–Lindau disease (modified from Maher [162]) is presented in table 2:

Screen for epididymal cystadenoma:Ultrasonography of the testes starting at 18 years.

Screen for ELST with audiogram:Biennial audiogram starting at age 16

Additional investigations in response to symptoms or signs of specific complications.

MOLECULAR ASPECTS IN VHL SYNDROME

Patients with VHL disease carry a germline mutation of the VHL tumor suppressor gene (VHL). The VHL gene had originally been linked to chromosome 3p25 in 1988 [163]and was subsequently cloned in 1993 [164]. The evolutionarily conserved VHL gene encodes two protein products, a 30-kDa full-length form (p30) and a 19-kDa form (p19).

The protein product of the VHL gene (pVHL) interacts with elongins B, C and Cullin-2 to form the VBC complex, an E3 ubiquitin ligase [165]. This multiprotein complex targets proteins for ubiquitin-mediated degradation, analogous to the S. cerevisiae SCF (Skp1/Cdc53/F-box) ubiquitination machinery [166-168]. Major targets of the VBC complex include the regulatory subunits of the heterodimeric transcription factor, hypoxia inducible factor (HIF). Therefore, VHL inactivation causes an up-regulation of HIF and downstream proteins under normoxic conditions. Many of the HIF targets are involved in the adaptation to acute or chronic hypoxia and include genes involved in the uptake and metabolism of glucose (GLUT-1), angiogenesis (VEGF, PDGF), control of extracellular pH (CA9), mitogenesis (TGFα), and erythropoiesis (erythropoietin)[169-172].

In addition to HIF degradation, the VHL protein is involved in HIF-independent cellular processes. It directs the proper deposition of fibronectin and collagen IV within the extracellular matrix [173]. Furthermore, it works to stabilize microtubules and foster the maintenance of primary cilium. The VHL protein also promotes the stabilization and activation of p53 and, in neuronal cells, promotes apoptosis by downregulation of Jun-B [173]. It was furthermore shown that acute VHL inactivation causes a senescent-like phenotype independently of HIF but dependent on the retinoblastoma protein (Rb) and the SWI2/SNF2 chromatin remodeler p400 [174].

Biallelic inactivation of the VHL tumor suppressor gene is suspected as initiating step of tumorigenesis. In general, two genetic events or “hits” are thought to occur to the two alleles of a tumor suppressor gene: The first hit is represented by a germline mutation and the second hit is characterized by inactivation of the wild-type allele [175]. More recent work suggests, that the biallelic VHL inactivation is only a first step in VHL tumorigenesis.

Current research for pharmacotherapy of VHL disease targets proteins of the HIF cascade [33]. Additionally investigated are compounds that lead to upregulation and re-functionalization of mutated VHL protein [177].